KR20100098491A - Agent for improving motor complications or psychiatric symptoms in parkinson's disease - Google Patents

Abstract

로 나타내는 화합물, 그 약리학적으로 허용되는 염 또는 이들의 수화물을 함유하는파킨슨병의 레보도파 치료에 수반되는 운동 합병증을 개선하고, 레보도파 치료에 수반되는 운동 합병증의 발증을 지연시키고, 파킨슨병의 증상의 진행을 억제 또는 지연시키는 약제가 제공된다. 화학식 (I)의 화합물은 세로토닌 1A 수용체 파샬 아고니스트 작용을 하는 동시에, 도파민 D2 수용체에 대하여는 안타고니스트 작용을 하지 않고, 도파민 D3 수용체에 대하여 아고니스트 작용을 하며, 레보도파 반복 투여에 수반되는 운동 합병증에 대하여 개선 및 발증의 지연 효과가 있고, 또한 진행기 파킨슨병 환자에 있어서 수반되는 정신증상에 대하여도 유효하다. Formula (I),

To improve the motor complications associated with levodopa treatment of Parkinson's disease containing a compound, a pharmacologically acceptable salt thereof, or a hydrate thereof, to delay the onset of motor complications associated with levodopa treatment, Agents are provided that inhibit or delay progression. Compounds of formula (I) act on serotonin 1A receptor partial agonist, do not antagonist action on dopamine D2 receptor, agonist action on dopamine D3 receptor, and respond to motor complications associated with repeated levodopa administration. There is an improvement and delay in onset, and it is also effective against psychiatric symptoms accompanying advanced stage Parkinson's disease patients.

Description

Drugs to improve motor complications or mental symptoms of Parkinson's disease {AGENT FOR IMPROVING MOTOR COMPLICATIONS OR PSYCHIATRIC SYMPTOMS IN PARKINSON'S DISEASE}

The present invention relates to a medicament for improving motor complications following levodopa treatment of Parkinson's disease, delaying the onset of motor complications following levodopa treatment, and inhibiting or delaying the progression of symptoms of Parkinson's disease. The present invention also relates to a medicament for ameliorating psychiatric symptoms associated with advanced stage Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder whose main symptoms are resting progression, congestion, motionlessness and postural reflex disorder. Parkinson's disease is classified into early onset Parkinson's disease and advanced stage Parkinson's disease. In other words, early Parkinson's disease refers to symptoms of relatively early onset without levodopa and dopamine receptor agonists, while advanced Parkinson's disease is already taking levodopa, and the problems with long-term use have emerged. Point to symptoms. The Japanese Neurological Society Treatment Guidelines (“The Japanese Neurological Association Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. Parkinson's disease treatment guidelines with efficacy and stability are described.

For Parkinson's disease, levodopa (chemical name: L-3,4-dihydroxyphenylalanine, also called L-DOPA) is the most effective therapeutic drug. Parkinson's disease is a progressive neurological disease caused by the specific degeneration and dropping of melanoma-progenitor dopamine neurons in the midbrain, and its main treatment is thought to be a supplement of insufficient dopamine. However, levodopa causes problems that are expressed as motor complications in Parkinson's disease patients with long-term use and make treatment difficult. This is a condition called advanced stage Parkinson's disease. Motor complications are wear-off phenomena in the daily fluctuations and motor fluctuations of dyskinesia and Parkinson's disease, which are interpreted as being due to levodopa's hyperactivity. , On-off phenomena, no-on / delayed on phenomena, etc. (“Neurological Society Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”). , Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94). Dyskinesia is a collateral movement associated with levodopa (which can be seen in the mouth, tongue, face, limbs, and trunk), which occurs when peak blood levels of levodopa are high. dose dyskinesia, and diphasic dyskinesia, which appear abnormally during the rise and fall of blood levels of levodopa, are all symptoms of excess of levodopa. In addition, a phenomenon called levodopa-induced dyskinesia (LID) in the sense of levodopa-induced is soon used well. Wearing-off phenomenon refers to a phenomenon in which the effect of levodopa disappears after several hours of taking levodopa due to shortening of the levodopa's effective time. The on / off phenomenon is a symptom that improves (on) or suddenly worsens (off) regardless of the levodopa dose, and the noon phenomenon is a phenomenon in which the effect is not manifested even when taking levodopa, and the delay-on phenomenon is levodopa. It is a phenomenon that takes time for the expression of the effect. These phenomena are all fluctuations in levodopa's on time (on period) and vice versa (off period: time when levodopa's effect is insufficient and Parkinson's disease symptoms occur). Variation or exercise variation (“The Japanese Neurological Association Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94). Once the motor complications of Parkinson's disease develop, once you switch to a different drug, you can't expect a recovery. For this reason, it has been reported that initiation of dopamine D2 receptor agonist rather than levodopa can reduce the risk of motor complications in the early stages of Parkinson's disease symptoms. However, it is only possible to obtain sufficient therapeutic effect with dopamine D2 receptor agonist alone. Difficult, coexisting with levodopa sooner or later will experience motor complications. (Murata Miho, “Drug Treatment of Wearing-Off Phenomenon”, Japanese Clinical, 2004, 62, p.1716-1719). Therefore, motor complications following levodopa therapy are still a major problem of Parkinson's disease treatment.

The main metabolic enzyme of levodopa in the body is dopa decarboxylase, but in addition to the metabolism of levodopa and dopamine, monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) are involved. In Parkinson's disease, the inhibitors of these metabolic enzymes increase the utilization of levodopa, and thus, the effect on the wear-off phenomenon, which is a shortening of the levodopa drug efficacy time in exercise complications, is expected. Monoamine oxidase (MAO) has subtypes of type A and B. Since human precursors have many types of B, inhibitors of monoamine oxidase B (MAO-B) are useful, and selegiline is clinically used. The effectiveness of the wear-off phenomenon of selegiline has been reported. (Golbe LI et al ., “Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease”, Clinical Neuropharmacology, 1988, 11, p. 45-55). Selegiline specifically inhibits monoamine oxidase B (MAO-B), which inhibits dopamine metabolism in the striatum and enhances the effect of levodopa. On the other hand, entacapone, which is a catechol-O-methyl transferase (COMT) inhibitor, is composed of levodopa as 3-O-methyl dopa (3-OMD) by the catechol-O-methyl transferase. By inhibiting the metabolic pathway, the loss of levodopa from the periphery can be delayed and the transition of levodopa into the brain can be maintained, thus exhibiting an effect on the wear-off phenomenon. (Parkinson Study Group, “Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients”, Annals of Neurology, 1997, 42, p. 747-755). All of these oxygen inhibitors exhibit clinical efficacy by enhancing and maintaining the effects of oral administration of levodopa, but at the same time, they may worsen for dyskinesia, which is thought to be based on the excessive action of levodopa. Indeed, in clinical trials of entacapone, the most frequent side effect is reported to be dyskinesia of motor complications (Mizuno Y. et al ., “Placebo-controlled, double-blind dose-finding study of entacapone in fluctuating pakinsonian patients ”, Movement Disorders, 2007, 22, p. 75-80). Therefore, this metabolic enzyme inhibitor does not satisfy the unmet needs of patients with advanced stage Parkinson's disease.

Antidepressant, anti-anxiety, and neuroprotective effects are known in the cellotonin 1A receptor agonist, but recently, the possibility of improvement in motor complications following levodopa treatment of Parkinson's disease has been reported (Nicholson SL & Brotchie). JM, “5-hydroxytryptamine (5-HT, serotonin) and Parkinson's disease-opportunities for novel therapeutics to reduce the problems of levodopa therapy”, European Journal Neurology, 2002, 9, p. 1-6). Although Parkinson's disease is a disease of the dopamine nervous system in the brain, why do we think that serotonin 1A receptor agonists, not dopamine receptor-related drugs, are effective in treating motor complications associated with levodopa therapy in Parkinson's disease? (1) In Parkinson's disease patients with motor complications, elevated blood peak concentrations of levodopa and shortening of half-life have been reported (Murata M. et al ., “Chronic levodopa therapy enhances dopa absorption: contribution to wearing- off ”, Journal of Neural Transmission, 1996, 103, p.1177-1185), (2) Serum levodopa concentration correlates well with dopamine concentrations in the brain, so with the progression of Parkinson's disease, dopamine concentrations in the brain change rapidly. (Murata M. et al ., “Chronic levodopa Therapy enhances Dopa Absorption: contribution to wearing-off”, Journal of Neural Transmission, 1996, 103, p.1177-1185), (3) It has been reported that levodopa administered from the periphery not only enters the dopamine nervous system but also enters the serotonin nervous system, where it has been converted and liberated therein. (Arai R. et al ., “Immunohistochemical evidence that central serotonin neurons produce dopamine from exogenous L-DOPA in the rat, with reference to the involvement of aromatic L-amino acid decarboxylase”, Brain Research, 1994, 667, p. 295-299, Yamada H. et al ., “Immunohistochemical detection of L-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulate in Parkinsonian model rats”, Neuroscience Research, 2007, 59, p.1- 7), (4) The release of dopamine derived from levodopa into the serotonin nervous system is likely to be regulated (inhibited) by the serotonin 1A receptor agonist, as is serotonin (Carta M. et al ., “Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in Parkinsonian rats”, Brain, 2007, 130, p. 1819-1833). In fact, serotonin 1A receptor agonists in ferns jotan (Olanow CW et al., " Multicenter, open-label, trial of sarizotan in Parkinson Disease patients with levodopa-induced dyskinesias (the SPLENDID Study)", Clinical Neuropharmacology, 2004, 27, p 58-62), Tandospiron (Kannari Kazuya et al., “Selective 5-HT1A Receptor Agonist, L-DOPA-induced dyskinesia Alleviation Effect of Citric Acid Tandonspiron”, Cranial Nerve, 2002, 54, p.133-137 And Bonifati V. et al ., “Buspirone in levodopa-induced dyskinesias”, Clinical Neuropharmacology, 1994, 17, p.73-82), have shown the efficacy of exercise complications associated with levodopa therapy in Parkinson's disease. Test results are reported. However, these drugs have an antagonist action on the dopamine D2 receptor as well as serotonin 1A receptor agonist action, and this action is expected to lead to attenuation of Parkinson's disease treatment effect by levodopa. Currently, in clinical trials, these drugs are reported to cause worsening of Parkinson's symptoms as a side effect. (Olanow CW et al ., “Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study)”, Clinical Neuropharmacology, 2004, 27, p.58-62, Kanari Kazuya et al. “Selective 5-HT1A Receptor Agonist, L-DOPA-induced dyskinesia alleviation effect of citric acid ballistic spiron”, Cranial Nerve, 2002, 54, p.133-137, Kleedorfer B. et al ., “Buspirone in the treatment of levodopa induced dyskinesias ”, Journal of neurology, neurosurgery, and Psychiatry, 1991, 54, p. 376-377).

Compound having agonist action on both serotonin 1A receptor and dopamine D2 receptor, 7- (1-{[5- (4-fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl)- Although 1,3-benzoxazole-2 (3H) -ondihydrochloride is disclosed in Japanese Unexamined Patent Publication No. 2005-298402, this compound has been used to evaluate L-DOPA-induced dyskinesia behavior in Parkinson's disease model rats. It is described that the dopamine stimulation score was increased with little increase in the Diskinesia score (Japanese Patent Laid-Open No. 2005-298402), and it can be predicted that neither the motor complications nor the symptoms of Parkinson's disease were improved.

In addition, serotonin 1A receptor agonists are classified as full agonists (complete agonists) and partial agonists (weak and partially activated than full agonists) in terms of their mode of action. 8-OH-DPAT as a 1A receptor pool agonist (chemical name: (R)-(+)-8-hydroxy-2- (di-n-propylamino) tetrarin), hereinafter referred to as 8-OH-DPAT. ), While Parkinson's disease marmoset has an inhibitory effect on dyskinesia induced by levodopa, it has been reported that at high doses, there is a reduction in the therapeutic effect of levodopa (Iravani MM et al ., “ In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with / increased motor disability ”, The Journal of Pharmacology and Experimental Th erapeutics, 2006, 319, p. 1225-1234). This means that it is difficult to set an appropriate dosage as a drug used in combination with levodopa therapy for setting a dosage scale according to the symptoms of the patient. In addition, the pool agonist is known to have a forgetful cause (健忘), a problem that is concerned when considering taking long-term.

Thus, in the treatment of levodopa in advanced stage Parkinson's disease patients, it is important to improve the motor complications, which are problematic without adversely affecting the treatment of Parkinson's disease by levodopa, but how to control the action on dopamine and serotonin nervous system It is not clear whether the desired effect is obtained.

In addition, Parkinson's disease is a progressive degenerative disease of the medulla-stratum dopamine nerve, and it is believed that the pathology worsens as the neurodegeneration progresses. Therefore, a large therapeutic effect can be expected as long as it can delay or regenerate the degeneration of the nitric-striated dopamine nerve. In Parkinson's disease models with water, serotonin 1A receptor agonists have neuroprotective effects and have been reported to delay the appearance of symptoms such as Parkinson's disease (Bezarde. Et al ., “5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease ”, Neurobiology of Disease, 2006, 23, p. 77-86). In addition, dopamine D3 receptor agonists reported neuroprotective activity (Joyce JN & Millan MJ, “Dopamine D3 receptor agonists for protection and repair in Parkinson's disease”, Current Opinion in Pharmacology, 2007, 7, p. 100-105) In recent years, it has also been suggested that it may have a protective and regenerative effect on the chromosomal-pigmentary dopamine neurons (Vankampen JM & Eckman CB, “Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior ”, The Journal of Neuroscience, 2006, 26, p.7272-7280). However, no drug has yet been successful in treating Parkinson's disease by delaying or regenerating nerve degeneration.

On the other hand, one of the problems in QOL of advanced stage Parkinson's disease patients is psychotic symptoms. As a non-motor symptom of Parkinson's disease, it has been reported to have psychosis in more than 60% (Aarsland D. et al ., “Range of neuropsychiatric disturbances in patients with Parkinson's disease”, Journal of neurology, neurosurgery, and psychiatry, 1999 , 67, p. 492-496). In addition, about 40% of Parkinson's disease patients are reported to be in a state of depression, and it has been pointed out that depression is the largest factor as an inhibitor of the quality of life of Parkinson's disease patients (Yamamoto Mitsutoshi, “Depression”, Japanese Clinical, 2004). , 62, p.1661-1666). In addition, symptoms of depression in Parkinson's disease are reported to be regarded as mild depression or mood modulation different from the depression as a mental illness due to rare symptoms such as suicide concern and suicide prayer (Veazey C. et al ., “Prevalence and treatment of depression in Parkinson's disease”, The Journal of Neuropsychiatry and Clinical Neurosciences, 2005, 17, p.310-323). In addition, hallucinations have been pointed out as psychotic symptoms worsening with the progress of Parkinson's disease. Hallucinations are reported to be recognized in about 20% of Parkinson's disease patients (Aarsland D. et al ., “Range of neuropsychiatric disturbances in patients with Parkinson's disease”, Journal of neurology, neurosurgery, and psychiatry, 1999, 67, p. 492-496). According to the Japanese Neurological Association's Treatment Guidelines, in the case of hallucinations, the principle is to gradually stop the anti-Parkinson's disease drug used until then, to simplify the prescription, and finally to treat only levodopa. In cases where it is difficult to reduce the number of patients, small amounts of atypical psychiatric drugs may be used (“The Japanese Neurological Society's Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94). In addition, side effects of atypical antipsychotics have been pointed out, and Parkinson's disease symptoms are also difficult to control, which has a great impact on the quality of life of patients. The pathological mechanism of hallucinations in Parkinson's disease is unknown, but the hypothesis interprets that dopamine receptors in the cerebral cortex are constantly being physiologically stimulated by excess dopamine, and abnormalities in serotonin function are involved in psychotic symptoms. The possibility of this is also indicated (Melamed E. et al ., “Involvement of serotonin in clinical features of Parkinson's disease and complications of L-DOPA therapy”, Advances in Neurology, 1996, 69, p.545-550). In fact, it has been reported that drugs that inhibit cerebral serotonin release have improved psychotic symptoms in advanced stages of Parkinson's disease (Zoldan J. et al ., “Psychosis in advanced Parkinson's disease: Treatment with ondansetron, a 5-HT3 receptor antagonist”). , Neurology, 1995, 45, p. 1305-1308). In addition, as behavioral disorders in patients with Parkinson's disease, anxiety and panic attacks have also been reported in addition to antidepression, and they may appear in synchronism with the off time, and thus, attention has been paid in thinking about conditions and treatments (Kashiwabara). Kenichi, “Behavioral Disorders”, Japanese Clinical, 2004, 62, p. 1675-1678).

Therefore, there is a need for a drug for treating Parkinson's disease, which is effective for improving psychological complications that are problematic in advanced stages of Parkinson's disease.

On the other hand, International Publication No. WO96 / 24594 discloses that some kind of benzoxazepine derivatives have strong affinity for serotonin receptor 5-HT1A, weak affinity for dopamine D2 receptor, and have anti-conflict activity as an index. It exhibits anti-anxiety action, has a protective effect in ischemic brain diseases such as cerebral infarction in the transient right middle cerebral artery occlusion (MCAO) model, anxiety neurosis, phobia, OCD, schizophrenia (currently called ataxia) Treatment for mental neurological disorders such as mental trauma after stress, antidepressant neuropathy, psychosis, eating disorders, menopausal disorders, diseases such as children's autism and vomiting, or diseases involving the cerebral circulatory system with cerebral infarction and cerebral hemorrhage. It is disclosed that it is useful for. In addition, Kamei K. et al ., “New 5-HT1A Receptor Agonists Possessing 1,4-benzoxazepine Scaffold Exhibit Highly Potent Anti-Ischemic Effects”, Bioorganic & Medicinal Chemistry Letters, 2001, 11, p. 595-598, Kamei K. et al ., “New piperidinyl-and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects”, Bioorganic & Medicinal Chemistry Letters, 2005, 15, p. 2990-2993 and Kamei K. et al ., “Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan”, Bioorganic & Medicinal Chemistry, 2006, 14 , p. 1978-1992 discloses a structural activity correlation of a benzoxazepine derivative having a strong affinity for serotonin receptor 5-HT1A and a weak affinity for dopamine D2 receptor.

Under the circumstances as described above, the problem of the present invention is effective for the treatment of the motor complications and the delay of the symptoms according to levodopa therapy, which is a big problem of advanced stage Parkinson's disease, and also effective for the psychological symptoms accompanying advanced stage Parkinson's disease, It is to provide a new treatment for Parkinson's disease, which is also expected to delay the progression of symptoms of Parkinson's disease.

According to the invention, formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 selected from the group consisting of methyl, methoxy and halogen atoms. Motor complications associated with levodopa treatment of Parkinson's disease, comprising a compound substituted with a substituent or represented by an unsubstituted phenyl group, pyridyl group, or pyrimidinyl group) or a pharmacologically acceptable salt thereof or a hydrate thereof A medicament for improving is provided.

BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the effect of the serotonin 1A receptor agonist on adenylic acid cyclase activity in rat hippocampal cell membrane products. Adenylate cyclase activity was measured by measuring the amount of cAMP produced by the same enzyme as an index, and the inhibition rate by serotonin 1A receptor agonist was determined by making the amount produced by forskolin (10 μM) stimulation as 100%. ± standard error (each group n = 5-9).
FIG. 2 is a diagram showing the effect of SUN N4057 single intraperitoneal administration on levodopa-derived striatum dopamine release in Parkinson's disease model rats (6 days of repeated administration of levodopa). FIG. Under anesthesia and no restraint, the amount of dopamine release from the rat striatum and the number of turns were measured using the microcranial dialysis method. That is, the striatum dopamine free amount (A) was measured every 20 minutes until 5 hours after levodopa intraperitoneal administration, and the rat turn count (B) for 5 minutes every 30 minutes after levodopa administration. SUN N4057 (3, 10 mg / kg) was administered intraperitoneally 20 minutes prior to levodopa (25 mg / kg) administration. The results are expressed as mean ± standard error (each group n = 2-4). * p <0.05, ** p <0.01: significant difference compared with physiological saline group (Dunnett's test).
Fig. 3 is a diagram showing hyperkinesia of the forelimbs that appeared after 5 weeks of repeated administration of levodopa in Parkinson's disease model rats. Hyperkinesia, such as involuntary flexion, appeared in the forelimbs on the fracture side (right) and on the opposite side (left). In addition, typical rat behavior was shown as a series of photographs after video shooting.
4 is a view showing the change in the turn behavior duration according to repeated administration of levodopa in Parkinson's disease model rats. The comparison between day 1 of levodopa administration and week 5 of repeated administrations is shown. On the 1st day of levodopa administration and the 5th week of repeated administration, the number of turns was measured every 5 minutes using a turning behavior measuring device, and the time which showed 20% or more of the maximum number of turns in each rat was calculated | required, and it was set as the turning behavior duration. The results were expressed as the mean value ± standard error of 28 cases in each group. *** p <0.001: significant difference comparing day 1 of levodopa administration and week 5 of repeated administration (Wilcoxon assay).
4 shows data before administration of SUN N4057 shown in FIGS. 5 and 6. Prior to administration of sarizotane shown in FIGS. 7 and 8 (37 cases in each group), Example compound 4 administration of JP 2005-298402 shown in FIGS. 9 and 10 (27 examples in each group) and SUN shown in FIGS. 13 and 14 Almost the same result was obtained even before administration of the N4057 flexible body (Compound Ib and Compound Ic) (37 examples in each group).
FIG. 5 shows the effect of SUN N4057 repeated subcutaneous administration on hyperkinesia of the forelimbs of Parkinson's disease model rats (week 7 repeated doses of levodopa). The onset time of the hypermotorosis of the forelimbs after levodopa administration at 7 weeks of levodopa repeated administration (2 weeks of SUN N4057 repeated subcutaneous administration) was measured, and the result was shown by the mean value ± standard error (each group n = 9-10). * p <0.05, ** p <0.01: significant difference compared with physiological saline group (Dunnett's test).
6 shows the effect of SUN N4057 repeated subcutaneous administration on the turning behavior of Parkinson's disease model rats (week 7 repeated doses of levodopa). At the 7th week of levodopa dosing (2nd week of SUN N4057 repeated subcutaneous dosing), the number of turns was measured every 5 minutes after levodopa administration using a turning behavior measuring device (A) and at least 20% of the maximum number of turns in each rat was determined. The time indicated was taken as the duration of turn behavior (B). The results are expressed as mean ± standard error (each group n = 9-10). * p <0.05, ** p <0.01: significant compared with physiological saline group (A: Dunnett's test, B: Dunnett's test joint type).
Figure 7 shows the effect of sarizotan repeated oral administration on hyperkinesia of the forelimbs of Parkinson's disease model rats (week 7 of levodopa repeated administration). The appearance time of the forefoot hyperkinesia after levodopa administration at 7 weeks of levodopa repeated administration (2 weeks of repeated oral administration of sarizotane) was measured, and the result was shown by the mean value ± standard error (each group n = 9 or 10). In addition, in the sarizotan 5 mg / kg pre-administration group, delay of the onset of rotational movement by levodopa administration was recognized, and 6 out of 9 cases 30 minutes after levodopa administration, and 9 cases after 1 hour of levodopa administration. Since the three examples did not show turning behavior, the overmovement of the forelimbs could not be measured. Therefore, the number of examples 30 minutes and 1 hour after levodopa administration in the 5 mg / kg combat sarizotan group was represented by n = 3 and n = 6, respectively. Significant difference compared to solvent administration group (Dunnett's test).
FIG. 8 shows the effect of sarizotan repeated oral administration on the turning behavior of Parkinson's disease model rats (week 7 repeated doses of levodopa). At the 7th week of levodopa repeated administration (2nd week of repeated oral administration of sarizotane), the number of turns was measured every 5 minutes after levodopa administration using a swing behavior measuring device (A) and at least 20% of the maximum number of turns in each rat was measured. The time indicated was taken as the duration of turn behavior (B). The results are expressed as mean ± standard error (each group n = 9-10). * p <0.05, ** p <0.01, *** p <0.001: significant difference compared with solvent administration group (A: Dunnett's test, B: Dunnett's test joint type).
FIG. 9 shows the effect of Example 4 repeated subcutaneous administration of Japanese Patent Laid-Open Publication No. 2005-298402 to hyperkinesia of the forelimbs of Parkinson's disease model rats (7 weeks of repeated administration of levodopa). The onset time of the hypermotorosis of the forelimbs after levodopa administration in the 7th week of levodopa repeated administration (Example compound 4 of JP 2005-298402, 2nd week of repeated subcutaneous administration) was measured, and the result was averaged ± standard error (each group). n = 9). Significant difference compared to physiological saline group (Dunnett's test).
10 shows the effect of Example 4 repeated subcutaneous administration of Japanese Patent Laid-Open Publication No. 2005-298402 on the turning behavior of Parkinson's disease model rats (week 7 of levodopa repeated administration). At the 7th week of levodopa repeated administration (Example compound 4 of Japanese Patent Application Laid-Open No. 2005-298402, 2nd week of repeated subcutaneous administration), the number of revolutions was measured every 5 minutes after levodopa administration using a swing behavior measuring device (A), and each rat The time which showed 20% or more of the maximum number of turns in was calculated | required, and it was set as turning turn duration (B). The results are expressed as mean ± standard error (each group n = 9). * p <0.05, ** p <0.01, *** p <0.001: significant compared with physiological saline group (A: Dunnett's test, B: Dunnett's test joint type).
FIG. 11 shows the effect of SUN N4057 sustained subcutaneous administration on levodopa dosing-induced turnover behavior using model rats of Parkinson's disease. During the levodopa dosing (7 weeks) period, the rat's turning behavior was recorded 1 hour after levodopa dosing. From week 6 repeated doses of levodopa, SUN N4057 or Alzet® infiltration pump (2ML4, dose 2ml, flow rate 2.5 μl / hr) infused with physiological saline was placed subcutaneously in the rat, followed by 1 week of levodopa administration. Subsequent rat turning behavior was recorded. The results are expressed as weekly turnover rate of levodopa repeated administration. The figure is shown by the mean value ± standard error (each group n = 8-9). * p <0.05, ** p <0.01: significant difference compared with physiological saline group (Dunnett's test joint type).
FIG. 12 shows the inhibitory effect of SUN N4057 on the appearance of hyperkinesia of levodopa repeat-induced forelimbs using model rats of Parkinson's disease. SUN N4057 (3 mg / kg) intraperitoneal administration was performed for 3 weeks with the initiation of repeated doses of levodopa and the time of appearance of hyperkinesia of the forelimbs was measured (A). In addition, after a three-week suspension period (only levodopa repeated administration was performed without a test substance), the appearance time of hyperkinesia of the forelimbs in the same rat was measured (B). The results are expressed as mean ± standard error (each group n = 5). ＃ p <0.05: significant difference (t test of correspondence) as compared to after the drug holiday.
13 shows the antidepressant effect of SUN N4057 evaluated using forced swimming. The dead time (A), the climbing action time (B), and the swimming action time (C) of 0-5 minutes (5 minutes) of the rats on the 2nd day of swimming were measured. The spontaneous movement amount (D) measures the spontaneous movement amount of the rat for 0-15 minutes (15 minutes) using the measuring apparatus installed in the light-shielding soundproofing box, and shows the result of the 5th minute. The results are expressed as mean ± standard error (each group n = 8). * p <0.05, ** p <0.01: significant difference compared with physiological saline group (Dunnett's test).
FIG. 14 shows the effect of compound Ib repeated intraperitoneal administration on hyperkinesia and turnover duration of forelimbs in Parkinson's disease model rats (week 7 repeated doses of levodopa). After the levodopa dosing at 7 weeks (compound Ib repeated intraperitoneal administration at 2 weeks), the appearance time of hypermotorosis of the forelimbs after levodopa administration was measured (A), and the number of revolutions was measured every 5 minutes after levodopa administration. The time which showed 20% or more of the highest turning number in the rat was calculated | required, and it was set as turning turn duration (B). The results are expressed as mean ± standard error (each group n = 5-6). * p <0.05, ** p <0.01, *** p <0.001: significant compared with physiological saline group (A: Dunnett's test, B: Dunnett's test joint type).
FIG. 15 shows the effect of compound Ic repeated intraperitoneal administration on hyperkinesia and turn behavior duration of forelimbs of Parkinson's disease model rats (week 7 repeated doses of levodopa). After 7 weeks of levodopa repeated administration (Compound Ic repeated intraperitoneal administration, 2 weeks), the appearance time of hypermotorosis of the forelimbs after levodopa administration was measured (A), and the number of turns was measured every 5 minutes after levodopa administration. The time which showed 20% or more of the highest number of turns in the rat was calculated | required, and it was set as the turning behavior duration (B). The results are expressed as mean ± standard error (each group n = 5-6). * p <0.05, ** p <0.01: significant compared with physiological saline group (A: Dunnett's test, B: Dunnett's test joint type).

The present inventors first conducted intensive studies to elucidate the relationship between the mechanisms of the occurrence of dyskinesia, a wear-off phenomenon and an on / off phenomenon associated with levodopa treatment of Parkinson's disease, and the action of the dopamine and serotonin nervous systems.

In addition, although serotonin 1A receptor agonists have been reported to improve motor complications, the present invention relates to the relationship between the action and the therapeutic effect of the serotonin 1A receptor agonists by inhibiting the steep rise in the striatum dopamine concentration after levodopa administration. By suppressing dyskinesia and maintaining the striatum dopamine concentration in the safe treatment area for a long time, the wear-off phenomenon can be reduced, and the neuronal protective action also inhibits the progressive degeneration of the striatum-striatum dopamine nerve. I assumed to do. In addition, serotonin 1A receptor agonists are classified as full agonists (complete agonists) and parshall agonists (weak and partially activated than full agonists) from their mode of action, but too high in full agonists when high doses are used. It acts strongly and is concerned about adversely affecting the treatment of Parkinson's disease by levodopa, and it becomes difficult to set a clinically appropriate dosage. I thought it was good because concerns could be resolved.

In addition, it is important not to have an antagonist action on the dopamine D2 receptor, which may lead to attenuation of Parkinson's disease treatment effect by levodopa, and on the dopamine D3 receptor, having an agonist action advantageously works for neuronal cell protection. Therefore, it was considered preferable.

Thus, a drug having a serotonin 1A receptor agonist (partial agonist) action and no antagonist action on the dopamine D2 receptor but agonist action on the dopamine D3 receptor was searched for. As a result, formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and W indicates the presence of a bond when carbon is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl, methoxy and halogen atoms Or a pharmacologically acceptable salt thereof, or a hydrate thereof (hereinafter referred to as a compound of the present invention), which is substituted with or represented by an unsubstituted phenyl group, a pyridyl group or a pyrimidinyl group). Found out.

The compound of the present invention is a compound described in International Publication WO96 / 24594, which has a strong affinity for serotonin 1A receptor, exhibits a weak affinity for dopamine D2 receptor, It exhibits anti-anxiety action based on the conflict action and has a protective function in ischemic brain diseases such as cerebral infarction in the transient right middle cerebral artery occlusion (MCAO) model, anxiety neurosis, phobia, OCD, nerve Involves schizophrenia (now called ataxia), mental traumatic stress disorder, antidepressant neuropathy, mental and neurological disorders such as psychosomatic disorders, eating disorders, menopausal disorders, childhood autism, and circulatory system involving vomiting or cerebral infarction and cerebral hemorrhage It is disclosed that it is useful for the treatment of the disease, and it also receives the serotonin 1A receptor and dopamine D2. Since the affinity for different, less side effects, it discloses that anti-depression, is useful as an anti-anxiety medication. However, International Publication No. WO96 / 24594 does not explain whether the compound of the present invention is full agonist, partial agonist, or agonist or antagonist for dopamine D2 receptor, and dopamine D3 for serotonin 1A receptor. The action on the receptor is not described at all, and there is no description of the therapeutic effect of motor complications or accompanying psychotic symptoms in the treatment of levodopa in Parkinson's disease, particularly in advanced stage Parkinson's disease.

In order to examine the therapeutic effects of motor complications and concomitant psychotic symptoms in patients with advanced stage Parkinson's disease, the present inventors made animal models with behavioral changes similar to motor complications, and examined the effects of the compounds. It has been found that there is an inhibitory effect of improvement and emergence on behavioral changes such as motor complications. In addition, it has been found that it is also effective against mental symptoms such as incidence and anxiety, and the present invention has been completed.

That is, the present invention provides the following.

(1) An agent for improving motor complications associated with levodopa treatment of Parkinson's disease, comprising the compound represented by the formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof.

(2) In the formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, or The drug according to the above (1), which represents an unsubstituted pyridyl group or pyrimidinyl group.

(3) The compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine-1 The agent according to the above (1), which is -yl] butyl} -1,4-benzoxazepin-5-one.

(4) The agent according to any one of (1) to (3) above, which reduces dyskinesia of motor complications associated with levodopa treatment of Parkinson's disease.

(5) The agent according to any one of (1) to (3), wherein the off time is reduced in levodopa treatment of Parkinson's disease.

(6) The medicament according to any one of (1) to (3), wherein in levodopa treatment of Parkinson's disease, the drug duration (on time) of levodopa that does not involve dyskinesia is extended.

(7) The agent according to any one of (1) to (3), wherein the frequency of on / off phenomenon of motor complications associated with levodopa treatment of Parkinson's disease is reduced.

(8) The medicament according to any one of (1) to (3), wherein the levodopa treatment of Parkinson's disease suppresses an increase in the therapeutically effective amount of levodopa accompanying the progression of symptoms.

(9) The medicament according to any one of (1) to (3), wherein the levodopa treatment of Parkinson's disease reduces the number of doses of levodopa per day effective for treatment.

(10) An agent which inhibits or delays the progression of symptoms of Parkinson's disease, which comprises the compound represented by the formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof.

(11) In the formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, or The agent according to the above (10), which is an unsubstituted pyridyl group or pyrimidinyl group.

(12) The compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine-1 The agent according to the above (10), which is -yl] butyl} -1,4-benzoxazepin-5-one.

(13) A drug for delaying the onset of motor complications associated with levodopa therapy of Parkinson's disease, which comprises the compound represented by the formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof.

(14) In the formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, or The drug according to the above (13), which is an unsubstituted pyridyl group or pyrimidinyl group.

(15) The compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine-1 The drug according to the above (13), which is -yl] butyl} -1,4-benzoxazepin-5-one.

(16) A medicament for improving the psychiatric symptoms associated with advanced stage Parkinson's disease, which comprises the compound represented by the formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof.

(17) In the formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, or The agent according to the above (16), which is an unsubstituted pyridyl group or pyrimidinyl group.

(18) The compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine-1 The agent according to the above (16), which is -yl] butyl} -1,4-benzoxazepin-5-one.

(19) The agent according to any of (16) to (18), wherein the psychotic symptoms associated with advanced stage Parkinson's disease are antidepressant, anxiety, or hallucinations.

(20) The above (1) to (1), wherein a combination of at least one agent selected from a peripheral dopa decarboxylase inhibitor, a monoamine oxidase B inhibitor, and a catechol-O-methyl transferase inhibitor is used. The drug described in any one of (19) ("combined with" herein) means that both drugs are administered at the same time, as a combination of both, or both drugs are independently independent in time. To administer).

(21) A pharmaceutical composition for treating Parkinson's disease, comprising (a) a compound represented by formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof and (b) levodopa.

(22) (a) the compound represented by the formula (I) or a pharmacologically acceptable salt thereof or a hydrate thereof, (b) levodopa and (c) peripheral dopa decarboxylase inhibitor, monoamine oxidase B inhibitor And one or more drugs selected from catechol-O-methyl transferase inhibitors.

(23) In the formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, or The composition as described in said (21) or (22) which is an unsubstituted pyridyl group or a pyrimidinyl group.

(24) The compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine-1 The composition according to the above (21) or (22), which is -yl] butyl} -1,4-benzoxazepin-5-one.

The compound of the present invention has a serotonin 1A receptor agonist (partial agonist) action, does not perform an antagonist action on the dopamine D2 receptor, and is used for repeated administration of levodopa from test results in a model rat of advanced stage Parkinson's disease described below. It has been found to show an improvement in the accompanying motor complications and an inhibitory effect on the appearance of motor complications and not to attenuate the action of levodopa. In addition, the compound of the present invention can suppress the steep rise of levodopa-derived dopamine concentration in Parkinson's disease patients, maintain the dopamine concentration in a safe treatment area for a long time, increase the utilization of levodopa, and accompany the progression of Parkinson's disease symptoms. It can be seen that suppressing an increase in the therapeutically effective amount of levodopa, which also reduces the number of therapeutically effective daily doses of levodopa, or suppresses an increase in the number of doses of levodopa. It has also been found that the compounds of the present invention also have an effect on the accompanying psychiatric symptoms in patients with advanced stage Parkinson's disease. In addition, the compounds of the present invention have been found not only to act on serotonin 1A receptor agonists (partial agonists) but also on a dopamine D3 receptor to inhibit the progression of symptoms of Parkinson's disease, a progressive neurodegenerative disease. It also proved to have a delaying effect. Moreover, the effect of the compound of this invention was seen in the clinical trial which examines the efficacy and safety as a therapeutic agent for exercise complications in Parkinson's disease patients receiving levodopa therapy. Therefore, the present invention enables the provision of a new Parkinson's disease therapeutic agent.

In the compound of the present invention represented by the general formula (I), a chlorine atom may be mentioned as a good example of the R ¹ group, and a hydrogen atom may be mentioned as a good example of the R ² group. Preferred examples of X include carbon atoms, where the dotted line indicates the presence of a bond. Moreover, as a preferable example of a group, an unsubstituted pyridyl group or a pyrimidinyl group substituted by the methyl group is mentioned, More preferably, a pyridyl group is mentioned.

As a specific particularly preferred embodiment of the compound represented by the general formula (I), 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetra Hydropyridin-1-yl] butyl} -1,4-benzoxazepin-5-one, 3-chloro-4,5-dihydro-4- {4- [4- (2-pyrimidinyl) -1 , 2,3,6-tetrahydropyridin-1-yl] butyl} -1,4-benzoxazepin-5-one and 3-chloro-4,5-dihydro-4- (4- {4- [ (4-methyl) -2-pyrimidinyl] -1,2,3,6-tetrahydropyridin-1-yl} butyl) -1,4-benzoxazepin-5-one, among which , 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridin-1-yl] butyl} -1,4- Especially preferred is benzoxazepin-5-one (compound of formula (II)).

In the present invention, pharmacologically acceptable salts include, in addition to inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrofluoric acid and phosphate, methanesulfonate, acetate, oxalate, succinate, maronate, tartarate, Organic hydrochloric acid such as maleate, fumarate, lactate and citrate, and the like, and hydrochloride and fumarate are preferred.

As a particularly preferred embodiment of the compound of the present invention, 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridin-1-yl ] Butyl} -1,4-benzoxazepin-5-one dihydrochloride dihydrate (compound Ia), 3-chloro-4,5-dihydro-4- {4- [4- (2-pyrimidy) Yl) -1,2,3,6-tetrahydropyridin-1-yl] butyl} -1,4-benzoxazepin-5-one hydrochloride (Compound Ib) and 3-chloro-4,5-dihydro- 4- (4- {4-[(4-methyl) -2-pyrimidinyl] -1,2,3,6-tetrahydropyridin-1-yl} butyl) -1,4-benzooxazepine-5 -On fumarate (compound Ic), and in particular, compound Ia (hereinafter referred to as SUN N4057) represented by the following formula (III) is used in motor complications or advanced stage Parkinson's disease accompanying levodopa treatment of Parkinson's disease. It is suitable for improving the accompanying mental symptoms.

The compound represented by the above formula (I) of the present invention, or a pharmacologically acceptable salt thereof or a hydrate thereof is disclosed in International Publication No. WO96 / 24594, Japanese Patent Laid-Open No. 2000-516640, Japanese Patent Laid-Open No. 2001-507373, Kamei K et al ., “A practical synthetic method for vinyl chlorides and vinyl bromides from ketones via the corresponding vinyl phosphate intermediates” Tetrahedron Letters, 2005, 46, p. 229-232 and Kibo (Kamei K. et al, above). ., “New 5-HT1A Receptor Agonists Possessing 1,4-benzoxazepine Scaffold Exhibit Highly Potent Anti-Ischemic Effects”, Bioorganic & Medicinal Chemistry Letters, 2001, 11, p. 595-598, Kamei K. et al ., “New piperidinyl-and1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects ”, Bioorganic & Medicinal Chemistry Letters, 2005, 15, p.2990-2993, Kamei K. et al ., “Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine deri vatives as selective 5-HT1A Receptor Agonists with neuroprotective effect: Discovery of Piclozotan ”, Bioorganic & Medicinal Chemistry, 2006, 14, p. 1978-1992).

The present invention provides a medicament that ameliorates the motor complications associated with levodopa treatment of Parkinson's disease. In the present invention, "improvement of motor complications" means motor symptoms that are recognized as a therapeutic problem in advanced stage Parkinson's disease patients, that is, motor complications (Dyskinesia, which is a secondary exercise accompanying levodopa therapy). And daily fluctuations or movement fluctuations of symptoms such as a wear-off phenomenon or an on / off phenomenon). Motor complications can be determined by the Unified Parkinson's Disease Rating Scale (UPDRS) Part 4: Complications of Therapy. Improvements in motor complications include a decrease in dyskinesia, a decrease in off time, an extension of the duration of medicament (on time) of levodopa that does not involve dyskinesia, and a decrease in the frequency of on / off symptoms. . Also included are inhibition of an increase in the therapeutically effective amount of levodopa accompanying the progression of symptoms and a reduction in the number of times of therapeutically effective daily administration of levodopa.

In the present invention, the term "reduced diskinesia" means the duration of dyskinesia, which is a secondary exercise associated with levodopa therapy seen in the mouth, tongue, face, limbs, and trunk (patient awakening time). It means that the ratio in which the weight is in the middle) is reduced, or the degree of the obstacle is reduced. Diskinesia can be determined by Part A of the Unified Parkinson's Disease Rating Scale (UPDRS) Part 4: Complications of Therapy (particularly paragraphs 32 and 33).

In the present invention, the term &quot; reduced off time &quot; means a ratio of off time (patient awakening time) at which time the effect of levodopa is insufficient and symptoms of Parkinson's disease (e.g., tremor, congestion, motionlessness, postural reflex disorder) appear. It means to reduce the ratio). The off time can be determined by Part B of the Parkinson's Disease Rating Scale (UPDRS) Part 4: Complications of Therapy (particularly 39).

In the present invention, "extending the duration (on time) of levodopa not involving diskinesia" is accompanied by the treatment of levodopa seen in patients with Parkinson's disease in the mouth, tongue, face, limbs and trunk. Percentage of time (on time) during which the symptoms of Parkinson's disease (e.g. progress, congestion, motionlessness, postural reflex disorder) are relatively invisible by taking levodopa, without experiencing dyskinesia, which is a concomitant exercise. To increase the ratio). Parkinson's disease symptoms can be determined by the Parkinson's Disease Rating Scale (UPDRS). Parkinson's disease patients may also be aware of the presence or absence of an effect after taking levodopa, that is, on or off.

In the present invention, "reducing the frequency of on / off phenomenon" refers to a phenomenon in which symptoms improve (on) or suddenly deteriorate (off) irrespective of the levodopa dose time (the time after medication). It means that the number of times that the on-off phenomenon appears is reduced. The on / off phenomenon may be repeated several times a day, and when it is on, it is reported that many people are accompanied by dyskinesia (“Japan Neurological Society Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”). ”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94).

Moreover, this invention provides "the suppression of the increase of the therapeutically effective amount of levodopa accompanying a progression of a symptom in the levodopa treatment of Parkinson's disease." Moreover, this invention provides "reducing the frequency of the daily effective dose of levodopa for the treatment of levodopa in Parkinson's disease." Levodopa is the most potent symptom-reducing agent among anti-Parkinson's disease drugs, and forms the core of Parkinson's disease. However, if the half-life of the drug is short (0.5 to 1 hour) and Parkinson's disease progresses, the duration of action of levodopa decreases, requiring higher doses of levodopa or multiple doses of levodopa to Parkinson's patients. . In some cases, it was necessary to increase from 2 to 3 times a day to 5 to 8 times at the start of levodopa treatment, which is a problem in the quality of life of the patient. In addition, levodopa is usually used as a peripheral dopa decarboxylase inhibitor combination (levodopa carbidopa mixture or levodopa bencerazide mixture, the daily use is usually 300 to 1200 mg) . Peripheral dopa decarboxylase inhibitors (carbidopa or benserazide) block the metabolism of levodopa to dopamine, but do not cross the blood brain barrier, and therefore do not inhibit dopamine metabolism in the brain. Do not. Since metabolism to dopamine in the peripheral is suppressed, the required amount of levodopa is reduced, and side effects of the digestive system are also reduced. This facilitates the introduction of treatments, while increasing the frequency of dyskinesia, which is thought to be caused by a sharp rise in striatum dopamine concentrations (“The Neurological Society's Guidelines for Treatment of Parkinson's Disease 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94). Based on the serotonin 1A receptor agonist (partial agonist) action, the compound of the present invention can suppress dyskinesia of motor complications by suppressing a sharp rise in the striatum dopamine concentration after levodopa administration. In addition, by keeping the dopamine concentration in the safe treatment area for a long time, the utilization rate of levodopa can be improved, and the increase in the therapeutically effective amount of levodopa accompanying the progression of Parkinson's disease symptoms is suppressed, and the therapeutically effective one day of levodopa is also effective. The number of doses can be reduced, or an increase in the number of doses can be suppressed. In the present invention, the term "reduce the therapeutically effective daily dose of levodopa" means that the increase in the number of doses of levodopa required as the progress of the symptoms is suppressed and the number of doses of levodopa already required is reduced. That means both.

The present invention also provides a medicament that inhibits or delays the progression of symptoms of Parkinson's disease. In the present invention, "inhibiting or delaying the progression of symptoms of Parkinson's disease" is a progressive degenerative disease of melanoma-progenitor dopamine neurons, and is related to Parkinson's disease in which the pathology worsens with progression of neurodegeneration. It means that the neurodegeneration can be suppressed or the neurodegeneration rate can be slower than usual based on the protective and regenerative action against the striatum dopamine nerve. The progression (severity) of symptoms of Parkinson's disease can be determined by the Hoehn & Yahr Staging and the Parkinson's Disease Rating Scale (UPDRS). If it is possible to delay or regenerate the degeneration of the stromal-predominant dopamine nerve in Parkinson's disease, a great therapeutic effect can be expected. However, no drug has yet been successful in treating Parkinson's disease by delaying or regenerating neurodegeneration. Indeed, even in the Japanese Neurological Society's Treatment Guidelines for Parkinson's Disease (“Japan Neurological Society's Treatment Guidelines for Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. If anti-Parkinson's disease is present, it is stated that it should be used as soon as it is diagnosed. Since the compound of the present invention has an agonist action on the dopamine D3 receptor and has a neuronal protective effect, it can inhibit or delay the progression of symptoms of Parkinson's disease.

The present invention also provides a medicament for delaying the onset of motor complications associated with levodopa treatment of Parkinson's disease. In the present invention, "delaying the onset of motor complications associated with levodopa treatment" means a dyskinesiana wear-off phenomenon and on / off phenomenon associated with long-term administration of levodopa in Parkinson's disease patients. This means delaying the onset of motor complications. In Parkinson's disease, the delay in the onset of motor complications, together with a medicament having a protective and regenerative action against the chromosomal-pigmentary dopamine nerve, has not yet been satisfied in the treatment of Parkinson's disease and is greatly desired. Although there is a wide range of reports of onset frequency of exercise complications following long-term levodopa in Parkinson's disease patients, about 40% of Parkinson's disease cases occur after 4 to 6 years of treatment (Ahlskog JE et. al ., “Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature”, Movement Disorders, 2001, 16, p. 448-458), and the Japanese Neurological Society's Treatment Guidelines for Parkinson's Disease (“Japanese nerves”). Parkinson's Disease Treatment Guidelines 2002 ”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94), also appeared almost 10% per year of initiation of levodopa treatment and 50% after 5 years. Patients are recorded suffering from intraday fluctuations in symptoms. In addition, the Japanese Neurological Society's Treatment Guidelines for Parkinson's Disease, except for some patients (aged 70 to 75 years and older and those with cognitive impairment), do not treat levodopa but dopamine D2 receptor agonists early in the onset of Parkinson's disease. It is recommended to start, but the main reason is to slow down the daily fluctuations of exercise symptoms and the occurrence of dyskinesia, and it is also important not to use more levodopa than necessary to slow the expected intraday fluctuations slightly. It is thought that. Based on the action of serotonin 1A receptor agonists (partial agonists), the compounds of the present invention can suppress the steep rise in the striatum dopamine concentration after levodopa administration and allow the striatum dopamine concentrations to remain in the safe treatment area for a long time. Therefore, by administering the compound of the present invention at the same time as the start of levodopa therapy, the utilization rate of levodopa can be increased, the therapeutically effective amount of levodopa can be kept at a low dose over a long period, and the onset of exercise complications can be delayed.

The present invention also provides a medicament for ameliorating the psychiatric symptoms associated with advanced stage Parkinson's disease. In the present invention, "improvement of mental symptoms" refers to the reduction or suppression of mental symptoms (depression, anxiety, hallucinations, etc.) among non-motor symptoms that are recognized as a therapeutic problem in advanced stage Parkinson's disease patients. it means. As described above, in Parkinson's disease, not only motor symptoms but also non-motor symptoms are pointed out as long-term treatment of Parkinson's disease and prolongation of the patient's life, which are factors that inhibit the quality of life of patients, and treatment for them is important. Psychotic symptoms can be determined by the Unified Parkinson's Disease Rating Scale (UPDRS) Part 1: Mental Function, Behavior and Mood. It is thought that incidence and anxiety in Parkinson's disease are highly likely to be due to motility disorders of patients. In the treatment of psychotic symptoms in advanced stage Parkinson's disease, antidepressants may be administered to suppress depression. Since tricyclic antidepressants may worsen Parkinson's disease, recently, selective serotonin reuptake inhibitors (SSRI) is mainstream. However, it has been reported that Parkinson's disease has been aggravated by the use of SSRI, and the combination of SSRI and monoamine oxidase B inhibitor selegiline may cause serotonin syndrome, which is contraindicated in Japan. (“Japan Neurological Society Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94). In addition, in the case of hallucinations in advanced stage Parkinson's disease, it is the principle to stop the anti-Parkinson's disease used in the treatment until now, simplify the prescription, and finally study the treatment only with levodopa, which reduces the amount of levodopa. If it is difficult to use a small amount of atypical antipsychotics. (“Japan Neurological Society Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p. 430-94) also pointed out the side effects of atypical antipsychotics and controlled Parkinson's disease symptoms. Also difficult to have a great impact on the quality of life of the patient. Although the pathogenesis of hallucinations is not known, hypothesis that the cortical dopamine receptors are constantly being stimulated non-physiologically by excessive dopamine, and the possibility of serotonin dysfunction may be involved in psychotic symptoms. (Melamed E. et al ., “Involvement of serotonin in clinical features of Parkinson's disease and complications of L-DOPA therapy”, Advances in Neurology, 1996, 69, p.545-550). In fact, it has been reported that drugs that inhibit cerebral serotonin release have improved psychotic symptoms in advanced stages of Parkinson's disease. (Zoldan J. et al ., “Psychosis in advanced Parkinson's disease: Treatment with ondansetron, a 5-HT3 receptor antagonist”, Neurology, 1995, 45, p. 1305-1308). In addition, as behavioral disorders in Parkinson's disease patients, anxiety and panic attacks have also been reported in addition to depression, and they may appear in synchronization with the off-time, attracting attention when considering a condition or treatment. (Kenichi Kashiwabara, “Action Disorder”, Japanese Clinical, 2004, 62, p. 1675-1678). The compound of the present invention does not reduce or weaken the therapeutic effect of levodopa, but rather increases the utilization rate, and also suppresses excessive stimulation of dopamine and suppresses cerebral serotonin release, thereby reducing the levodopa treatment effect in patients with advanced stage Parkinson's disease. I can improve mental symptoms without weakening.

Hereinafter, although an Example demonstrates this invention concretely, it cannot be overemphasized that the scope of the present invention is not limited to these Examples.

SUN N4057 shows strong binding affinity with a Ki value of 0.0249 nM for the human serotonin 1A receptor as shown in Example 1, but Ki values of 161 nM and 162 for the human dopamine D2L receptor and dopamine D2S receptor, respectively. Only weak binding affinity was shown with nM. In addition, the dopamine D2 receptor has two subtypes depending on the presence or absence of 29 amino acid residues in the third loop in the cell, and is called D2 Long (denoted D2L) and D2 short (denoted D2S), and D2L is synapse posterior. D2S is present in all of the synops respectively. As shown in Example 2, as a function, SUN N4057 has agonist action (EC50 values: 2.41 nM and 2.12 nM, respectively) on human serotonin 1A receptor and human dopamine D3 receptor, but human dopamine D2L receptor and There is no antagonist action (EC50 value:> 500 nM) on the D2S receptor. In the treatment of Parkinson's disease, levodopa and dopamine D2 receptor agonists are used as therapeutic drugs, and the dopamine D2 receptor antagonist action may cause a reduction in the Parkinson's disease therapeutic effect. Therefore, SUN N4057 without dopamine D2 receptor antagonist action does not reduce the levodopa therapeutic effect of Parkinson's disease, and can be expected to have an effect based on serotonin 1A receptor and dopamine D3 receptor agonist.

Serotonin 1A receptor agonists are also classified as full agonists (complete agonists) and parshall agonists (weak and partially activated than full agonists) in terms of their mode of action, but at high doses, full agonists It is too powerful to be concerned that it adversely affects the treatment of Parkinson's disease by levodopa. In fact, 8-OH-DPAT, a representative serotonin 1A receptor pool agonist, exhibits inhibitory action against levodopa induced by levodopa in Parkinson's disease marmoset, but at high doses, it has no effect on levodopa's therapeutic effect. It has been reported (Iravani MM et al ., “In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+) -8-OHDPAT inhibits levodopa-induced dyskinesia but only with / increased motor disability ”, The Journal of Pharmacology and Experimental Therapeutics, 2006, 319, p.1225-1234). At this time, as shown in Example 3, a full agonist partial agonist discrimination test was performed on the serotonin 1A receptor of SUN N4057 using the rat hippocampus, and it was found that SUN N4057 was a serotonin 1A receptor partial agonist. Even when high doses are used, for example, it has been found to be less likely to adversely affect the treatment of Parkinson's disease by levodopa.

As is well known, Parkinson's disease is a progressive degenerative disease and the condition worsens with the progression of neurodegeneration. Delaying the progression of neurodegeneration by the administration of drugs is another unmet and greatly desired matter of Parkinson's disease. In contrast, in model monkeys of Parkinson's disease, serotonin 1A receptor agonists have been reported to delay the appearance of symptoms such as Parkinson's disease (Bezarde. Et al ., “5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease ”, NeuroBiology of Disease, 2006, 23, p. 77-86). In addition, dopamine D3 receptor agonists are known for neuronal protective action (Joyce JN & Millan MJ, “Dopamine D3 receptor agonists for protection and repair in Parkinson's disease”, Current Opinion in Pharmacology, 2007, 7, p. 100-105). In recent years, it has been suggested that not only protective but also regenerative action may be performed on the degenerative and degenerating nitric-striated dopamine neurons specifically in Parkinson's disease (Van Kampen JM & Eckman CB, “Dopamine D3 receptor agonist). delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior ”, The Journal of Neuroscience, 2006, 26, p.7272-7280). SUN N4057 has a serotonin 1A receptor agonist (partial agonist) action and also has an agonist action for the dopamine D3 receptor. Thus, these reports indicate that SUN N4057 is useful as a novel Parkinson's disease therapeutic agent with the effect of delaying the progression of symptoms of Parkinson's disease based on the protective action on the nitric-progenitor dopamine neurons.

As shown in Example 4, after repeated administration of levodopa to a unilateral black matter-protease dopamine neurodestructive rat, which is commonly used as an animal model of Parkinson's disease, the amount of dopamine free from rat progenitors and the number of rat turns from the rat striatum were used. The effect of SUN N4057 on was reviewed. As a result, SUN N4057 exhibited an inhibitory effect on the increase in the amount of levodopa-derived dopamine release and delayed the peak time of the dose of dopamine release, which decreased after 30 minutes of levodopa administration in rats, but at 150-210 minutes after levodopa administration. Increased inversely. Further, judging from the amount of dopamine release in the striatum of normal rats examined using the same method, it was thought that the dopamine release amount of SUN N4057 brought the levodopa-derived dopamine release to a more normal concentration range. This indicates that SUN N4057 has an action of inhibiting the increase in the steep streptodopamine-free amount derived from levodopa in Parkinson's disease patients and staying within a more normal concentration range.

As shown in Example 5, model rats of advanced stage Parkinson's disease were constructed by repeat administration of levodopa, using unilateral black matter-striated dopamine neurodestructive rats, which are commonly used as animal models of Parkinson's disease, and accompanied by levodopa repeated administration. After examining the effects of hyperkinesia of the forelimbs (abnormal behavior such as dyskinesia in the clinical) and shortening of the duration of turning behavior (phenomena such as wear-off in clinical), SUN N4057 exhibits significant inhibitory action of hyperkinesia of the forelimbs and prolonged shortened turn behavior duration. This results in SUN N4057 reducing dyskinesia and reduced off time of motor complications associated with levodopa treatment in Parkinson's disease patients, prolonging the duration (on time) of levodopa that does not involve dyskinesia It shows what is useful as a medicament.

As shown in Example 6, SUN N4057 showed an improvement effect on the response failure of Parkinson's disease model rats reported to be similar to the on / off phenomenon in advanced Parkinson's disease patients. This suggests that SUN N4057 is useful as an agent for reducing the frequency of on / off symptoms of motor complications associated with levodopa therapy in Parkinson's disease patients.

Parkinson's disease is a progressive degenerative disease of the warp-total streptococcal dopamine nerve, and it is thought that the pathology worsens with the progression of neurodegeneration. Motor complications associated with long-term levodopa administration have been reported to occur in about 40% of Parkinson's patients after 4-6 years of treatment (see Ahlskog JE et al ., Movement Disorders, 2001, 16, p.448-458). As shown in Example 7, hyperkinesia of the forelimbs appearing with levodopa repeated administration by performing repeated administration of SUN N4057 in combination with levodopa repeated administration in Parkinson's disease model rats. Abnormal behavior such as) was suppressed. This indicates that SUN N4057 also has an effect of delaying the onset of dyskinesia associated with levodopa treatment in Parkinson's disease patients.

In addition, the present invention, as shown in Example 8, significantly reduces the downtime, which is an indicator of antidepressant action in the forced swimming test, without affecting the spontaneous momentum in rats, as well as swimming behavior. It was found to indicate an increase in time. In the rat forced swimming test, drugs that significantly reduce inactivity time and increase in swimming behavior time are said to have a strong effect of improving mood (depression, anxiety) in clinical practice. (Katz MM et al ., “Drug-induced Actions on brain neurotransmitter systems and changes in behaviors and emotions of depressed patients” Neuropsychopharmacology, 1994, 11, p. 89-100). In addition, the symptom of congestion in Parkinson's disease is considered to be a mild depression or mood modulation that differs from Daeul's disease as a mental disorder because symptoms such as suicide concern and suicide attempts are rare (Veazey C. et al. , “Prevalence and treatment of depression in Parkinson's disease”, The Journal of Neuropsychiatry and Clinical Neurosciences, 2005, 17, p.310-323). Therefore, SUN N4057 can be expected to have a more appropriate action against incidence and anxiety seen in Parkinson's disease patients. It suggests what we have together. In addition, hallucinations have been pointed out as psychotic symptoms that also worsen the progression of Parkinson's disease. Hallucinations are reported to be recognized in about 20% of Parkinson's disease patients (Aarsland D. et al ., “Range of neuropsychiatric disturbances in patients with Parkinson's disease”, Journal of neurology, neurosurgery, and psychiatry, 1999, 67, p 492-496). Although the pathogenesis of hallucinations in Parkinson's disease patients is unknown, it is interpreted that the dopamine receptors in the cerebral cortex are constantly being stimulated nonphysiologically by excess dopamine, but there is also a possibility that abnormalities in serotonin function may be involved. It is. (Melamed E. et al ., “Involvement of serotonin in clinical features of Parkinson's disease and complications of L-DOPA therapy”, Advances in Neurology, 1996, 69, p.545-550, Zoldan J. et al ., “Psychosis in advanced Parkinson's disease: Treatment with ondansetron, a 5-HT3 receptor antagonist ”, Neurology, 1995, 45, p. 1305-1308). In other words, it is hypothesized that hallucinations in patients with Parkinson's disease result from excessive stimulation of the serotonin nervous system in the brain associated with long-term levodopa administration. This hypothesis shows that hallucinations in patients with advanced stage Parkinson's disease were significantly suppressed by drugs that inhibit serotonin release in the brain (Melamed E. et al ., “Involvement of serotonin in clinical features of Parkinson's disease and complications of L-DOPA). therapy ”, Advances in Neurology, 1996, 69, p. 545-550). Serotonin 1A receptor agonists are known to inhibit serotonin in the brain, and these reports suggest the possibility of SUN N4057 inhibiting hallucinations associated with levodopa therapy in advanced Parkinson's disease.

Next, as shown in Example 9, also about compound Ib and compound Ic which are the soft bodies of SUN N4057, the model rat of advanced stage Parkinson's disease was constructed, and the hypermotor syndrome of the front leg which appears with levodopa repeated administration ( As a result of examining the effects on abnormal behavior such as dyskinesia in clinical practice and shortening of the duration of turning behavior (phenomena such as wear-off in clinical), the effect of significant forelimbs in any compound was observed. It has been shown to inhibit the movement and to prolong the shortened turn behavior duration. This indicates that the compounds of the present invention are useful as agents to ameliorate the dyskinesia and wear-off phenomenon of motor complications associated with levodopa treatment in Parkinson's disease patients.

Moreover, as shown in Example 10, according to the clinical trial which examines the efficacy and safety of SUN N4057 as a therapeutic agent for exercise complications in Parkinson's disease patients receiving levodopa treatment, the compound of this invention is made into 1) dyskinesia. Increase the duration (on time) of levodopa that does not accompany it; and 2) reduce the off time, which is a time when levodopa's effects are insufficient and symptoms of Parkinson's disease (e.g. progress, constriction, motionlessness, postural reflex disorder) appear. And 3) have been shown to have an effect of improving the severity of dyskinesia without prolonging the off time, and also not causing the worsening of Parkinson's disease symptoms.

The compound of the present invention can be administered in combination with a levodopa preparation. That is, the compound of the present invention may be administered during levodopa treatment, for example, may be administered simultaneously to each time of levodopa administration for one day, or may be administered once every multiple times of levodopa administration. The levodopa preparation may be either a levodopa preparation or a levodopa-peripheral dopa decarboxylase inhibitor compounding agent. Examples of peripheral dopa decarboxylase inhibitors include carbidopa or benserazide.

In addition, according to the present invention, the compound of the present invention can be used in combination with or in combination with a levodopa agent, using either or both of a monoamine oxidase B inhibitor and a catechol-O-methyl transferase inhibitor. Treating the disease was also assumed. Although not limited, the monoamine oxidase B inhibitor may include selegiline, and the catechol-O-methyl transfer enzyme inhibitor may include entacapone.

A compound of the present invention, a levodopa alone or a levodopa-peripheral dopa decarboxylase inhibitor combination agent, and optionally one or both of a monoamine oxidase B inhibitor and a catechol-O-methyl transferase inhibitor The compositions to be prepared are prepared by methods well known in the art.

When applied as a medicament, the compound of the present invention can be administered orally or parenterally. Pharmaceuticals containing the compounds of the invention include, for example, tablets (including dragees and film-coated tablets), powders, fine granules, granules, capsules, powders, suspensions, injections, suppositories, and sustained release drugs. Etc. may be sufficient. In addition, as the most suitable formulation for oral administration, tablets, powders, fine granules, granules, and capsules are preferred depending on Parkinson's disease patients. These formulations are adjusted in accordance with conventional methods (for example, the method described in the two Japanese defenses).

Specifically, the method for preparing a tablet is granulated in a suitable manner by adding the drug as it is, and adding an excipient, binder, disintegrant, or other suitable additives, and then adding a lubricant, compression molding or drug Is prepared by direct compression molding of an admixture with an excipient, a binder, a disintegrating agent or other suitable additives, or by mixing uniformly with pre-prepared granules or by adding an appropriate additive and then compression molding It can manufacture. Moreover, this agent can add a coloring agent, a copper, etc. as needed. In addition, the present agent can form the coating of the formulation with a suitable coating agent.

The preparation of capsules is generally carried out in accordance with conventional methods by combining the compounds of the present invention with hard oral preparation carriers to fill hard gelatin capsules, soft capsules and the like.

In the preparation method of injectables, a certain amount of the medicine is used, and in the case of an aqueous solvent, in the case of non-aqueous solvents such as injection water, physiological saline, and Ringer's solution, it is generally dissolved, suspended or emulsified in vegetable oil, etc. It can be manufactured by sealing in a container for injection.

As the oral preparation carrier, for example, substances commonly used in the preparation field, such as starch, mannite, crystalline cellulose and sodium carboxymethylcellulose, are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, fluid, and the like are used. In addition, additives used in general formulations may be appropriately added.

The dosage of the compound of the present invention varies depending on the route of administration, the dosage form, the number of administrations, the age, the weight of the patient, and the degree of symptoms, etc. More preferably, 1 to 5 mg may be administered once or twice or more in divided portions. In the case of parenteral administration, it is good to administer 1/10 thru | or amount, preferably 1/10 thru | or 2/2 amount in the case of oral administration.

Example

Hereinafter, although an Example demonstrates this invention further more concretely, it cannot be overemphasized that the scope of the present invention is not limited to these Examples. In addition, saarizotan (1-[(2R) -3,4-dihydro), which is a serotonin 1A receptor agonist and has been reported to have clinical trials showing effectiveness in motor complications associated with levodopa therapy in Parkinson's disease -2H-chromen-2-yl] -N-{[5- (4-fluorophenyl) pyridin-3-yl] methyl} methanamine dihydrochloride) and agonists on both serotonin 1A receptor and dopamine D2 receptor Japanese Patent Laid-Open Publication No. 2005-298402, which reported that there was an effect, and that dopamine stimulation scores were improved with little increase in dyskinesia scores in L-DOPA-induced dyskinesia behavior evaluation in Parkinson's disease model rats. Example compounds described 4 (7- (1-{[5- (4-fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1,3-benzooxazole-2 (3H ) -One dihydrochloride) was used.

Example  1: human serotonin 1A receptor, human dopamine D2 L receptor, human dopamine D2S receptor and human dopamine D3  Binding affinity test for receptor

1-1. Binding Affinity Test for Human Serotonin 1A Receptor

For the test, a membrane product prepared from human serotonin 1A receptor expression Chinese hamster ovary (CHO-K1) cells was used. [ ³ H] 8-hydroxy-2- (di-n-propylamino) tetrarin in 50 mM Tris-HCl (pH 7.4) buffer containing 5 mM CaCl ₂ , 0.1% ascorbic acid and 10 μg / mL saponin ([ ³ H] 8-OH-DPAT) (final concentration 1 nM), test substance solution, and membrane target were added. After the reaction solution was reacted at 25 ° C. for 60 minutes, the reaction solution was filtered by a cell harvester, the filtered filtrate was transferred to a measuring vial bottle, a liquid scintillator was added, and the receptor binding radioactivity remaining on the filter paper was liquid scintillated. It measured by the radar counter. Nonspecific binding was made with the amount of binding in the presence of 10 μM serotonin.

Binding inhibition was calculated by the following equation.

Binding inhibition rate (%) = 100-100 × {[Amount of [ ³ H] 8-OH-DPAT binding in the presence of the test substance]-[[ ³ H] 8-OH-DPAT binding in the presence of 10 μM serotonin]} / { [piheom material absent ^{[3 H] 8-OH-} DPAT binding amounts under ^{a] - [[3 H] 8} -OH-DPAT binding amounts under 10 μM serotonin present]}

From the binding inhibition rate, a 50% inhibition concentration was calculated by the regression equation, and the inhibition constant (Ki) was also calculated.

1-2. Person dopamine D2 Binding affinity test for L receptor

For the test, a membrane product prepared from human dopamine D2L receptor expression Chinese hamster ovary (CHO) cells was used. In 50 mM Tris-HCl (pH 7.4) buffer containing 1.4 mM ascorbic acid, 0.001% BSA and 150 mM NaCl, [ ³ H] spiferon (final concentration 0.16 nM), test substance solution and membrane target were added. After reacting the reaction solution at 25 ° C. for 2 hours, the reaction solution was filtered by a cell harvester, the filtered filter paper was transferred to a measuring vial bottle, a liquid scintillator was added, and the receptor binding radioactivity remaining on the filter paper was liquid scintillated. It measured by the radar counter. Nonspecific binding was the amount of binding in the presence of 10 μM haloperidol.

Binding inhibition was calculated by the following equation.

Under - {[10 μM haloperidol exist under ^[3 H] RY Peron bond content] ^[[3 H] substance exists under piheom RY Peron bond content]} / {[piheom material absent binding inhibition rate (%) = 100-100 × ^[3 H] RY Peron bonding amount] - [10 μM haloperidol exist under ^[3 H] RY Peron bond content]}

From the binding inhibition rate, a 50% inhibition concentration was calculated by the regression equation, and the inhibition constant (Ki) was also calculated.

1-3. Person dopamine D2S  Binding affinity test for receptor

For the test, a membrane product prepared from human dopamine D2S receptor expression Chinese hamster ovary (CHO) cells was used. [50 H Tris-HCl (pH 7.4) buffer containing 1.4 mM ascorbic acid, 0.001% BSA and 150 mM NaCl, [ ³ H] spiferon (final concentration 0.16 nM), test substance solution and membrane target were added. After reacting the reaction solution at 25 ° C. for 2 hours, the reaction solution was filtered by a cell harvester, the filtered filter paper was transferred to a measuring vial bottle, a liquid scintillator was added, and the receptor binding radioactivity remaining on the filter paper was liquid scintillated. It measured by the radar counter. Nonspecific binding was the amount of binding in the presence of 10 μM haloperidol.

Binding inhibition was calculated by the following equation.

Under - {[10 μM haloperidol exist under ^[3 H] RY Peron bond content] ^[[3 H] substance exists under piheom RY Peron bond content]} / {[piheom material absent binding inhibition rate (%) = 100-100 × ^[3 H] RY Peron bonding amount] - [10 μM haloperidol exist under ^[3 H] RY Peron bond content]}

From the binding inhibition rate, a 50% inhibition concentration was calculated by the regression equation, and the inhibition constant (Ki) was also calculated.

1-4. Person dopamine D3  Binding affinity test for receptor

In the test, a membrane product prepared from human dopamine D3 receptor expression Chinese hamster ovary (CHO) cells was used. In 50 mM Tris-HCl (pH 7.4) buffer containing 1.4 mM ascorbic acid, 0.001% BSA and 150 mM NaCl, [ ³ H] spiron (final concentration 0.7 nM), test substance solution and membrane target were added. After the reaction solution was reacted at 37 ° C. for 2 hours, the reaction solution was filtered by cell harvest, the filtered filter paper was transferred to a measuring vial bottle, a liquid scintillator was added, and the receptor binding radioactivity remaining on the filter paper was liquid scintillated. It measured by the radar counter. Nonspecific binding was made with the amount of binding in the presence of 25 μM S (−)-sulfide.

Binding inhibition was calculated by the following equation.

Binding inhibition rate (%) = 100-100 × {[ [3 H] RY Peron bond content material is present under piheom] - [25 μM S (- ) - alkylsulfinyl lead under the presence ^[3 H] RY Peron bond content]} / { [Amount of [ ³ H] Spiferon Binding in the Absence of Test Substance]-[[ ³ H] Spiferon Binding Amount in the Presence of 25 μM S (−)-Sulfide]]

From the binding inhibition rate, a 50% inhibition concentration was calculated by the regression equation, and the inhibition constant (Ki) was also calculated.

Table I

Table I shows binding affinity for human serotonin 1A receptor, human dopamine D2L receptor, human dopamine D2S receptor and human dopamine D3 receptor. For the human serotonin 1A receptor, all test substances showed strong binding affinity, and SUN N4057 and sarizotan showed particularly strong binding affinity. On the other hand, for human dopamine (D2L, D2S and D3) receptors, sarizotan and Example compound 4 of JP 2005-298402 showed relatively strong binding affinity.

Example  2: human serotonin 1A receptor, human dopamine D2 L receptor, human dopamine D2S receptor and human dopamine D3  For receptors Agonist · Antagonist  exam

Tests include human serotonin 1A receptor expression Chinese hamster ovary (CHO-K1) cells, human dopamine D2L receptor expression Chinese hamster ovary (CHO) cells, human dopamine D2S receptor expression Chinese hamster ovary (CHO) cells and human dopamine D3 receptor expression Chinese A membrane product prepared from hamster ovary (CHO) cells was used. In the agonist test, [ ³⁵ S] GTPγS (final concentration 0.1 nM) in 20 mM Hepes-NaOH (pH 7.4) buffer containing 100 mM NaCl, 3 mM MgCl ₂ and 10 μg / mL saponin for serotonin 1A receptor. , A GDP solution (final concentration 3 μM), a test substance solution and a membrane target were added and reacted at 25 ° C. for 30 minutes. In addition, for the dopamine (D2L, D2S and D3) receptors in [ ³⁵ S] GTPγS (20 mM Hepes-NaOH, pH 7.4) buffer containing 100 mM NaCl, 10 mM MgCl ₂ , 1 mM DTT and 1 mM EDTA. Final concentration 0.1 nM), GDP solution (final concentration 3 μM), test substance solution and membrane product were added and reacted at 30 ° C. for 15 minutes (for D2L receptors) or 30 minutes (for D2S and D3 receptors). In addition, in the antagonist test, the reaction solution contains 10 μM 5-carboxamide tributamine (5-CT) (for serotonin 1A receptor), 3 μM dopamine (for D2L and D2S receptor) or 0.1 μM dopamine ( The same operation as the agonist test was performed except that the D3 receptor was added). After completion of the reaction, the reaction solution was filtered by a cell harvest, the filtered filter paper was transferred to a measuring vial bottle, a liquid scintillator was added, and the radioactivity of [ ³⁵ S] GTPγS remaining on the filter paper was measured by a liquid scintillation counter. . The human serotonin 1A receptor and human dopamine (D2L, D2S and D3) receptor agonist-antagonist activity of each test substance were 10 μM 5-CT (for serotonin 1A receptor) and 3 μM dopamine (for D2L and D2S receptors), respectively. Or [ ³⁵ S] GTPγS binding increase by 0.1 μM dopamine (for D3 receptor) at 100%. 50% reaction concentration (EC50) and 50% inhibition concentration (IC50) were calculated by the regression equation from the increase in binding.

Table II-1

Table II-2

Table II-3

Table II-4

Tables II-1 to II-4 show the results of agonist-antagonist tests for human serotonin 1A receptor, human dopamine D2L receptor, human dopamine D2S receptor and human dopamine D3 receptor. With respect to the human serotonin 1A receptor, all test substances showed agonist activity, and the activities of SUN N4057 and sarizotan were particularly strong. On the other hand, no antagonist activity was seen. For both the human dopamine D2L receptor and the D2S receptor, almost no agonist activity was observed, while sarizotan and Example compound 4 of JP 2005-298402 showed antagonist activity. In addition, regarding the human dopamine D3 receptor, Example compound 4 of SUN N4057 and JP 2005-298402 showed strong agonist activity, but no antagonist activity. Sarizotane, on the other hand, does not exhibit agonist activity against human dopamine D3 receptors, but exhibits weak antagonist activity.

From these results, it was clear that SUN N4057 had a potent human serotonin 1A receptor agonist action, and did not have an antagonist action on the human dopamine D2 receptor and an agonist action on the human dopamine D3 receptor.

Example  3 ： Rat  Adenylate Mediated by Serotonin 1A Receptor Cyclase  Suppression Test (Pool Agonist · Parshall Agonist  Discrimination test)

In Example 3, 8-OH-DPAT and {2- [4- (4-pyrimidin-2-ylpiperazin-1-yl) butyl] -1,2-benzothiazol-3 (2H) -one 1,1-dioxide} (hereinafter referred to as incident pylon). 8-OH-DPAT is well known as a representative serotonin 1A receptor pool agonist, and incidence pyron is a representative serotonin 1A receptor partial agonist.

For the test, Wistar male rats supplied by Shimizuji Kenken Co., Ltd. were used (9-15 weeks of age). Rats were headed and the hippocampus was quickly fractionated. Homogenized in 10-fold buffer (25 mM Tris-HCl, 1 mM EGTA, 5 mM EDTA, 5 mM DTT, 300 mM sucrose, 100 KIU / ml aprotinin, pH 7.4). It centrifuged for 5 minutes at 500xg and 4 degreeC, The supernatant was centrifuged for another 10 minutes at 39,000xg and 4 degreeC, and the precipitation residue was used as the rat hippocampal membrane product. Rat hippocampal membrane specimens were diluted with buffer to a protein of 20-90 μg / mL, and 50 μL of this cell membrane suspension was diluted with 200 μL of assay buffer (25 mM Tris-HCl, 100 mM NaCl, 2) containing each test substance. mM MgCl ₂ , 0.25 mM ATP, 5 mM phosphocreatin, 10 μg / mL creatine phosphokinase, 0.2 mM IBMX, 10 μM GTP, 10 μM forskolin, pH 7.4), and reacted at 30 ° C. for 5 minutes. The reaction was stopped by adding 250 µL of 0.2 N HCl, and the resulting cAMP was quantified by radio immunoassay. Regression equations from the concentration-response curves yielded a 50% inhibitory concentration (IC 50) for the maximum response. In addition, adenylate cyclase activity was measured using the amount of cAMP produced by this enzyme as an index, the amount produced by forskolin (10 μM) stimulation was 100%, and the inhibition rate by serotonin 1A receptor agonist was determined. It was.

SUN N4057 concentration-dependently inhibited adenosyl cyclase activity stimulated with forskolin and the maximum inhibitory response was 20% (IC 50 = 2.67 nM). The concentration of the partial agonist, pyrron, and full agonist, 8-OH-DPAT, also inhibited adenylate cyclase activity, and the maximum inhibitory responses were 19% (IC50 = 38.95 nM) and 32% (IC50 = 14.82 nM, respectively). (Fig. 1). In addition, their action was completely antagonized by WAY-100635 (100 nM), a selective antagonist of the serotonin 1A receptor.

From these results, it was found that SUN N4057 acts as a partial agonist for serotonin 1A receptors in the serotonin acting neurosynaptic thick film. In Example 3, SUN N4057 was a partial agonist with respect to the serotonin 1A receptor, whereas in Example 2, the same results as in the full agonist were obtained. This difference is considered to be attributable to the expression level of the serotonin 1A receptor. In Example 2, a system in which the human serotonin 1A receptor was strongly expressed in the cell was used, and about 100-fold of the serotonin 1A receptor was present as compared with the membrane product produced from the rat. Serotonin 1A receptor parshall agonists have been reported to act as full agonists when the ratio of receptors to G protein increases (Newman-Tancredi A et al ., “Agonist and inverse agonist efficacy at human reconbinant serotonin 5). -HT1A receptors as a function of receptor: G-protein stoichiometry ”, Neuropharmacology, 1997, 36 (4-5), p. 451-459), so that SUN N4057 is applied to the human serotonin 1A receptor expressing cells of Example 2. It is interpreted as showing the same result as a full agonist.

Example  4: Parkinson's disease model Rat  ( Levodopa  6 days of repeated administration) re Sidewalk origin Striatum  SUN for Dopamine Glass N4057 Single Intraperitoneal  Effect of administration ( Anesthetic Without restriction  Test using micro brain dialysis)

Parkinson's disease treatment guidelines (“Japan Neurological Society's Treatment Guidelines Parkinson's Disease Treatment Guidelines 2002”, Ad Hoc Committee, Clinical Neurology, 2002, 42, p.430-94) suggest that Parkinson's disease is relatively mild in early Parkinson's disease and levodopa. Long-term use is distinguished by advanced stage Parkinson's disease causing therapeutic problems. At this time, after repeated administration of levodopa to a unilateral nigerous-stratum dopamine neurodestructive rat, which is widely used as an animal model of Parkinson's disease, SUN N4057 single-shot for the amount of dopamine release from rat striatum and the number of rat turns from the rat striatum using microcranial dialysis. The effect of intraperitoneal administration was examined.

Crl: CD (SD) male rats (8 weeks of age at the start of the test) supplied from Charles River, Japan were used for the production of model rats of Parkinson's disease by unilateral black matter-stratum dopamine nerve destruction. Rat tofu under anesthesia after pentobarbital (40 mg / kg) intraperitoneal administration with nocipinemin resorption inhibitor desipramine (25 mg / kg) about 30 minutes prior to 6-hydroxy dopamine infusion. The cerebrum was fixed to the cerebral stereotactic fixation device. 6-hydroxydopamine (total amount 8 μg / 4 μL) containing ascorbic acid was dissolved in physiological saline, and the right inner forearm (1.8 mm posterior to bregma, 2.0 mm right from median line, two cranial) And then injected into the two portions of depth 8.3 mm and rearward 4.5 mm from bregma, 1.4 mm from right midline and depth of 8.5 mm from cranial) at a flow rate of 1.0 μL / min through a micro injection needle, followed by Incubated for 5 minutes.

In order to confirm the success of dopamine neurodestruction after about 3 weeks of the surgery, the rat's turning behavior after subcutaneous administration of apomorphine (0.05 mg / kg), a dopamine receptor agonist, was rotated in a behavior measuring device (rotor meter 6 ch system). And Muromachikai Co., Ltd.). One hour infusion immediately after administration of apomorphine means that rats with more than 100 turns to the opposite side were judged to have completed unilateral chromosomal-stratified dopamine neuronal destruction and were used in subsequent tests.

In addition, from about one week thereafter, rats received repeated intraperitoneal administration of levodopa (25 mg / kg) + benzoserazide (10 mg / kg), a peripheral dopa decarboxylase inhibitor (hereinafter, referred to as levodopa repeated administration) ( Twice a day, Monday to Friday) for six weeks.

Guided cannula induction for microdialysis was performed under pentobarbital (40 mg / kg intraperitoneal) anesthesia, after fixing the head of the rat to the cerebral stereotactic fixation device (0.5 mm anterior from bregma, from midline). A microcancer dialysis guide cannula (3.0 mm on the right, 4.0 mm from the cranial depth) was inserted, and two rats were fixed using dental cement. The next day, under anesthesia and without restraint, a microelectrodialysis probe (PC12, Carnegie Medicin, outer diameter 0.5 mm, dialysis membrane length 3.0 mm, cut off 20000 Daltons) was inserted through the guide cannula and Ringer's solution (NA ⁺ , 147). was, 155.6 mM, pH 6.5) a small amount of perfusion with 1.5 μL / min (Carnegie Medicin claim ^{CMA100) - Cl; mM; K} +, 4 mM; CA 2 +, 2.3 mM. After about 3 hours of probe insertion (start of microperfusion), perfusion solution was collected every 20 minutes in a sample tube to which 5 μL of antioxidant (0.1 M perchloric acid, 0.1 mM disodium EDTA, 0.1 mM sodium metasulfite) was added. Five samples (100 minutes) are taken before levodopa dosing and 15 samples (300 minutes) after levodopa dosing, and the resulting perfusate is a high-performance liquid chromatography system (LC-EC D) equipped with an electrochemical detector. Dopamine concentration was measured using. In addition, the number of turns on the side opposite to the 6-hydroxydopamine injection side was measured visually for 5 minutes every 30 minutes after levodopa administration. SUN N4057 (3, 10 mg / kg) was administered intraperitoneally 20 minutes prior to levodopa (25 mg / kg) administration.

In addition, the bioavailability of SUN N4057 in rats is good at about 100% in subcutaneous administration, but low at about 27% in intraperitoneal administration, and rapidly disappears as a peak 15 minutes after administration. Therefore, in the intraperitoneal administration, a higher dose was set than the subcutaneous administration.

As a result, the pre-intraperitoneal administration of SUN N4057 (3, 10 mg / kg) confirmed an inhibitory effect on the increase in the amount of levodopa-derived striatum dopamine, and the peak time of the dopamine release was delayed (Fig. 2-A). In addition, the number of turns of rats decreased after 30 minutes of levodopa administration, but increased in reverse at 150 to 210 minutes of levodopa administration (Fig. 2B). Dopamine release in the striatum of normal rats examined using the same method was found to be 9.24 ± 0.65 (pg / 20 min), and the levodopa-derived dopamine release from SUN N4057 was close to the normal concentration range. It was thought. Therefore, it has been suggested that SUN N4057 has an effect of suppressing an increase in the amount of levodopa-derived steep dopamine free in Parkinson's disease model rats and keeping it within a more normal concentration range.

Example  5: Model of Parkinson's disease Rat  Used Levodopa  Repeated administration Triggering front Leg Hyperkinesia  Assessment test for shortening of turn and turn behavior duration

It has been found that, in unilateral black-line striatum dopamine neurodestructive rats, which have been widely used as an animal model of Parkinson's disease, a similar behavior appears in the symptoms of advanced stage Parkinson's disease by repeated administration of levodopa for 5 weeks. That is, in Parkinson's disease model rats constructed in the same manner as in Example 4, involuntary flexion, hand opening and closing, and wrists on the foreleg on the side opposite to the micro-injection side of 6-hydroxy dopamine with repeated administration of levodopa Abnormal behavior such as tremors such as up and down, painless pain was recognized (Fig. 3). These abnormal behaviors were described by Steece-Collier K et al ., “Embryonic mesencephalic grafts increase levodopa-induced forelimb hyperkinesia in Parkinsonian Rats,” Movement Disorders, 2003, 18, p.1442-1454. It has been reported as hyperkinesia, appears depending on the levodopa repeat dosing period, and is reported to be similar to clinical dyskinesia. In addition, when the turning behavior was compared between the first day of levodopa administration and the fifth week of repeated administration, the duration of the turning behavior (the time at which the number of turns at the fifth minute was measured for each rat, and 20% or more of the maximum turning number was shown) was shortened. (Figure 4). Bibiani et al . (Bibbiani F et al ., “Serotonin 5-HT1a agonist improves motor complications in rodent and primate parkinsonian models”, Neurology, 2001, 57, p. 1829-1834), have been shown to repeat the levodopa administration in Parkinson's disease model rats. Accompanied by the reduction in turn behavior duration, it is reported that this phenomenon is similar to the wear-off phenomenon in the clinic.

At this time, in the same manner as in Example 4, Parkinson's disease model rats were constructed, and levodopa repeated administration (twice daily, Monday to Friday) was performed for 5 weeks, followed by levodopa administration for 30 minutes, Observations were made for 2 minutes at each time after 1 and 2 hours, and the time (seconds) showing abnormal behavior was recorded. The turning behavior of the same rats was measured using a turning behavior measuring device every 5 minutes from immediately after levodopa intraperitoneal administration to 4 hours later, as described by Bibiani et al . (Bibbiani F et al ., Neurology, 2001, 57, p. 1829-1834), the time which represented 20% or more of the highest number of turns in each rat was calculated | required, and it was set as the turning behavior duration.

In addition, based on the results of hypermotorosis and turn behavior duration of the forelimbs, the rats were assigned to develop significant differences between the groups, and then the effect of the test substance on these behaviors similar to those in patients with advanced stage Parkinson's disease. Was compared and reviewed. That is, repeated administration of the test substance was performed for about two weeks (Monday to Friday) together with repeated administration of levodopa to each group, and hyperkinesia and turning behavior of the forelimbs after levodopa administration were observed. In addition, SUN N4057 was administered subcutaneously before and after levodopa administration, and sarizotane was administered orally about 20 minutes prior to levodopa administration according to the report described above (Bibbiani F et al ., Neurology, 2001, 57, p. 1829-1834). And Example 4 of JP 2005-298402 was administered subcutaneously about 30 minutes before levodopa administration according to JP 2005-298402. As a solvent, physiological saline was used for Example Compound 4 of SUN N4057 and Japanese Unexamined Patent Publication No. 2005-298402, and sarizotan was used for physiological saline containing 0.3% Tween80 because its solubility was poor.

As a result, SUN N4057 (0.03 mg / kg) significantly inhibited the overexertion of the forelimb 1 hour after levodopa administration, and in SUN N4057 (0.1 mg / kg), overexertion of the forelimb 1 and 2 hours after levodopa administration Symptoms were significantly suppressed (FIG. 5). The turning behavior after levodopa administration was significantly extended by the end of the turn by SUN N4057 (0.03, 0.1 mg / kg) (Fig. 6-A), and the turn behavior duration obtained from the number of turns was significantly extended (Fig. 6-A). B). Therefore, it has been suggested that SUN N4057 is effective against dyskinesia and wear-off phenomenon in patients with advanced stage Parkinson's disease.

By 5 mg / kg of sarizotane, hyperkinesia of the forelimb 1 hour after levodopa administration showed a tendency to be suppressed (p = 0.099) (FIG. 7). In addition, with sarizotane 1 and 5 mg / kg, delay of the onset of turning exercise by levodopa administration is recognized (FIG. 8A), and sarizotane 5 mg / kg is significant for the turning behavior duration obtained from the number of turns. Shortening was recognized (Fig. 8-B). Therefore, it was suggested that in the patients with advanced stage Parkinson's disease, sarizotane is unlikely to suppress motor complications without reducing the therapeutic effect of levodopa.

As Example Compound 4 (1, 3 mg / kg) of JP 2005-298402 A, it showed an effect on hyperkinesia of the forelimbs of rats after levodopa administration (FIG. 9). However, with respect to the turning behavior after levodopa administration, Example Compound 4 (1.3 mg / kg) of JP 2005-298402 A started the turnaround and extended the end of the turn (FIG. 10 -A). Regarding the turning behavior duration obtained from the number of turns, a significant extension was recognized in the 3 mg / kg administration group (Fig. 10-B). Therefore, although Example compound 4 of Unexamined-Japanese-Patent No. 2005-298402 may have an effect with respect to a wear-off phenomenon among the motor complications induced by levodopa, it was suggested that it was ineffective for Dyskinezia.

Example  6: Model of Parkinson's disease Rat  Used Levodopa  administration Triggering  Test for turning behavior manifestations

Papa SM et al ., “Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration”, Brain Research, 1994, 662, p. 69-74). In response to the administration of levodopa, rats that do not exhibit turning behavior are observed irregularly, and this phenomenon is called response failure, and this phenomenon is called on / off in patients with advanced stage Parkinson's disease. It is reported to be similar to the phenomenon.

At this time, the same model rats of Parkinson's disease as in Example 4 were constructed, and the rats were subjected to levodopa repeated administration (twice a day, Monday to Friday) for 7 weeks. During repeated doses of levodopa, the presence or absence of turning behavior was recorded every rat individual 1 hour after levodopa administration. As a result, at the first week of levodopa repeated administration, almost all rats exhibited a turning behavior after levodopa administration, but rats exhibiting no turning behavior even after 2 weeks of levodopa repeated administration were observed. At this time, the rats were recorded every 1 to 5 weeks of repeated levodopa administration, and then Alzet (registered with SUN N4057 or physiological saline injected from the 6th day of levodopa repeated administration in order to examine the effect of the test substance). Infiltration pressure pump (2ML4, dose 2 ml, flow rate 2.5 μl / hr) was implanted subcutaneously in rats. For 2 weeks thereafter, rats were continuously recorded whether or not the rat had a turning behavior 1 hour after levodopa administration.

As a result, in the physiological saline sustained subcutaneous administration group, the turning behavior expression rate tended to decrease with repeated levodopa administration, but the SUN N4057 sustained subcutaneous administration group showed a recovery effect of the turning behavior expression rate (FIG. 11). In addition, the measured values of SUN N4057 plasma concentrations in each group measured after completion of the behavioral experiments were 5.3 ± 0.7 ng / mL in the SUN N4057 low-dose sustained subcutaneous group and 14.3 ± 2.9 ng / mL in the high-dose sustained subcutaneous group.

These results suggest that SUN N4057 can expect an improvement effect on the on / off phenomenon in advanced stage Parkinson's disease patients.

Example  7: Model of Parkinson's disease Rat  Of used forelimbs Hyperkinetic  Test of inhibitory effect on appearance

By repeatedly administering levodopa to a model rat of Parkinson's disease, it was possible to observe forefoot hyperkinesia (aberrant behavior such as dyskinesia in clinical) (see FIG. 3). At this time, it was examined whether the occurrence of hyperkinesia of the forelimb could be suppressed by repeat administration of the test substance from the beginning along with the start of repeated administration of levodopa.

The same model rats of Parkinson's disease as in Example 4 were constructed, and intraperitoneal administration of physiological saline or SUN N4057 (3 mg / kg) was performed for three weeks (Monday to Friday) with the start of repeated administration of levodopa. Hyperkinesia of the forelimbs was observed in the same manner as in step 5. The test substance was administered intraperitoneally about 20 minutes before levodopa administration. Thereafter, a three-week washout period (only levodopa repeated administration without administration of the test substance) was set, and hyperkinesia of the forelimbs in the same rat was observed in the same manner.

As a result, by intraperitoneal administration of SUN N4057 (3 mg / kg) with the initiation of repeated administration of levodopa, the appearance of hyperkinesia of the forelimbs in model rats of Parkinson's disease was reduced and compared with the results after the drug holiday period. Significant inhibitory effect was recognized (FIGS. 12-A, B). Therefore, SUN N4057 suggested the possibility of suppressing or delaying the onset of dyskinesia associated with long-term levodopa administration in Parkinson's disease patients.

Example  8: using forced swimming Antidepression  Evaluation test of the effect

The test was carried out using a Crl: CD (SD) male rat supplied from Nippon Charles River (6 weeks of age at the start of the test). Lucki I, “The forced swimming test as a model for core and component behavioral effects of antidepressant drugs”, Behavioural Pharmacology, 1997, 8, p.523-532; Cryan JF et al ., “Assessing Cylindrical cylinders filled with water on day 1 using an improved method reported by antidepressant activity in rodents (recent developments and future needs ”, TRENDS in Pharmacological Sciences, 2002, 23, p.238-245). cm x 30 cm, depth 30 cm, water temperature 23 ° C., depth was set to the depth where the rear leg and tail of the rat did not reach the bottom), and the rat was removed after 15 minutes. At this time, 10-15 minutes (5 minutes) of inactivity time (seconds) were recorded, and based on the result, rats were divided into 5 groups so that there was a difference in each group. On day 2, the rats were placed in a cylindrical cylinder filled with water as in day 1, and the 0-5 minutes (5 minutes) of inactivity time (seconds), swimming action time (seconds) and climbing action time (seconds) were measured. . In addition, the idle time is the minimum movement of the rat to keep the head above the surface, the swimming action moves horizontally in the cylinder, the swimming action, and the climbing action moves the forelimb up and down along the cylinder wall. It was action. The test substance was administered intraperitoneally 15 minutes after the end of swimming on day 1, and 4 hours and 30 minutes before swimming on day 2. In addition, the spontaneous momentum of the rat was determined to be zero by spontaneous momentum of the rat by using a measuring device (shape 48.8 × 48.8 × 30 cm, 64 fractions in total length, 8 fractions in length, 8 fractions in width, and Kabushiki Kaisha Biomedica) installed in the shading soundproof box. -15 minutes (15 minutes) were recorded. In addition, the dose and the timing of administration of the test substance were set in the same manner as the forced swimming test and administered intraperitoneally 24 hours, 4 hours and 30 minutes before the spontaneous exercise measurement.

As a result, SUN N4057 (0.3, 1, 3 mg / kg) showed a significant shortening of dose-free time, and decipramine (10 mg / kg), which is well known as an antidepressant, A short axis was shown (Fig. 13A). In addition to no downtime, the climbing and swimming behavior time was measured, indicating that significant increase in climbing behavior time (FIG. 13 -B) by desipramine (10 mg / kg) was observed in SUN N4057 (1, 3 mg / kg). ), A significant increase in swimming behavior time was observed (FIG. 13-C). Spontaneous momentum was reduced to 0-5 minutes (5 minutes) by desipramine (10 mg / kg). However, there was no significant change in SUN N4057 (0.3, 1, 3 mg / kg) (FIG. 13 -D).

Forced swimming test is widely used as a preclinical evaluation method because antidepressants have the effect of reducing downtime. In addition, in the improved forced swimming test, the inactivity time is reduced by any drug that indicates the activation of the norepinephrine nervous system or the serotonin nervous system, but the climbing behavior time is determined by the drug indicating the activation of the norepinephrine nervous system. In addition, the swimming behavior time has been reported to increase with drugs that indicate activation of the serotonin nervous system (Cryan JF et al ., “Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test”, European Journal of Pharmacology, 2002, 436, p. 197-205). In clinical practice, antidepressants that activate the norepinephrine nervous system are motivated, have a strong effect of reactivating stagnant mental movements (slow motion, anguish expression, deactivation, reduced speech), and serotonin nervous system. Antidepressants that activate the drug have been shown to have a strong effect on improving mood (anxious mood, anxiety) (see Katz MM et al ., Neuropsychopharmacology, 1994, 11, p. 89-100).

SUN N4057 does not affect spontaneous momentum, shows significant shortening of downtime, and increases swimming behavior time. Therefore, it has been suggested that SUN N4057 has an antidepressive effect and exhibits an improvement effect on mood (depression, anxiety), which has been pointed out as the greatest factor as an inhibitor of quality of life in Parkinson's disease patients.

Example  9: Model of Parkinson's disease Rat  Used Levodopa  Repeated administration Triggering forelimbs of Hyperkinesia  And compounds for reducing turnover duration Ib  And compounds Ic Behavioral assessment test

Using the same method as in Example 5, the compound Ib and the compound Ic were observed for hyperkinesia and turning behavior of the forelimbs after levodopa administration. A model rat of Parkinson's disease was constructed in the same manner as in Example 4, and rats were subjected to levodopa repeated administration (twice a day, Monday to Friday) for 5 weeks, and the rat's forelimb hyperkinesia and turning behavior were measured. In addition, based on the results of hypermotorosis and turn behavior duration of the forelimbs, rats were assigned to develop significant differences between the groups, and then the effect of the test substance on these behaviors was similar to those of patients with advanced stage Parkinson's disease. Comparative review was made. That is, repeated administration of the test substance was performed for about two weeks (Monday to Friday) together with repeated administration of levodopa to each group, and hyperkinesia and turning behavior of the forelimbs after levodopa administration were observed. In addition, Compound Ib (0.3, 1 mg / kg) and Compound Ic (0.3, 1 mg / kg) were both administered intraperitoneally before and after levodopa administration, and physiological saline was used as a solvent.

As a result, compound Ib (0.3, 1 mg / kg) significantly inhibited hyperkinesia of the forelimbs 30 minutes and 1 hour after levodopa administration (Fig. 14-A), and also extended turn behavior duration obtained from the number of turns. The tendency to become is shown (FIG. 14-B). In addition, the compound Ic (0.3, 1 mg / kg) significantly inhibited the overexertion of the forelimbs 30 minutes after levodopa administration at 0.3 mg / kg, and the excess of the forelimbs 30 minutes and 1 hour after levodopa administration at 1.0 mg / kg. The motility was significantly suppressed (Fig. 15-A), and the turning behavior duration obtained from the number of turns was also significantly extended at 1.0 mg / kg (Fig. 15-B). Therefore, it was suggested that Compound Ib, a SUN N4057 softener, may have an improvement effect on Diskinezia in advanced stage Parkinson's disease patients, and Compound Ic on Diskinezia and wear-off phenomenon.

Example  10 ： Levodopa  SUN as an exercise complication medicine in Parkinson's disease patient treated N4057 Clinical trials reviewing the effectiveness and safety of

Way:

The efficacy of SUN N4057 for motor complications associated with levodopa therapy in patients with Parkinson's disease was reviewed by multilingual, double-blind, randomized placebo control and exploratory testing. Eligible patients meet the United Kingdom Parkinson's Disease Society (UKPDS) cerebral protein diagnostic criteria, have Hoehn & Yahr staging at “off” 2 to 4 degrees, and have Parkinson's disease. Patients from 40 to 85 years old who have been treated with a combination of levodopa and carbidopa or a combination of monodose at a constant dosage for at least five years after the diagnosis and at least 30 days prior to administration of the test drug. It was set as.

After implementing the Informed Concept, subjects were screened (period 9-22 days prior to scheduled start of dosing). During the screening period, the patient continued with previous antiparkinsonism drug treatment, including the combination of levodopa-carbidopa or a combination of single agents. Eligible patients were those who exhibited a therapeutic effect in which the score (number of points) of the Part 3 (motor function test) of the Unified Parkinson's Disease Rating Scale (UPDRS) improved at least 25% compared to prior to the administration by medication. .

At baseline (8 ± 2 days before the scheduled start date of dosing), subjects received an 8 hour in-hospital evaluation. After the first visit, the first anti-Parkinson drug (including a combination of levodopa / carbidopa or a combination of monotherapy) begins eight hours after about one hour of treatment, and evaluates the state of movement every hour (“Diskinesia Evaluation of "on" or "off" without "Dinskinegia" accompanied by an evaluation, evaluation of part 3 of the Parkinson's Uniform Rating Scale (UPDRS), symptom of dyskinesia As an evaluation, an abnormal incident movement scale (AIMS) was evaluated.

Subjects who completed the screening and baseline evaluation were randomly divided into one of the SUN N4057 dose group and the placebo dose group at a ratio of 3: 1. Each subject received SUN N4057 (target blood concentration 30 ng / mL) or placebo for 12 days of intravenous continuous infusion for 2 days. The dose was controlled to reach the target concentration 1 hour after initiation of administration and to maintain 11 hours, with the average SUN N4057 dose of the administered patients being 13.123 mg on day 1 and 9.550 mg on day 2.

Assessment of exercise status (“on with diskinesia”) on day 1 of administration of test drug, prior to treatment with the first anti-Pakison drug (including combination of levodopa / carbidopa or combination of monotherapy) Evaluation of on ”or“ off ”without the following), part 3 of the Parkinson's disease unification scale (UPDRS), and evaluation of abnormal incident motor scale (AIMS). A 12 hour intravenous sustained infusion of SUN N4057 or placebo was initiated after antiparkinson drug treatment. During the evaluation period of 8 hours from the start of infusion, the evaluation of the exercise state, the evaluation of Part 3 of the Parkinson's disease unification scale (UPDRS), and the abnormality of the exercise scale (AIMS) were performed every hour.

result:

Between the test groups, no significant difference in demographic and baseline characteristics was seen.

In the SUN N4057 dosing group, the ratio of on time without dyskinesia, the ratio of on time with dyskinesia, and the ratio of off time were 41.0%, 49.3%, and 9.7% in the evaluation on the second day, respectively. The ratio of on time not involving dyskinesia is increased by 22.2 points (41.0-18.8) in comparison with the baseline, and the ratio of off time is reduced by 11.1 points in comparison with the baseline (9.7 20.8) (Table III).

The ratio of on time without dyskinesia in the placebo dose group, the ratio of on time with dyskinesia, and the ratio of off time were 12.5%, 6.63% and 23.2% in the evaluation on the second day, respectively. However, the ratio of on time not involving dyskinesia is not recognized as a change in comparison with the baseline (12.5-12.5), whereas the ratio of off time is an increase of 14.3 points in comparison with the baseline (23.2 -8.9) (Table III).

Table III

 In addition, the proportion of patients (responders) whose off-time was not prolonged and the symptom of dyskinesia, which was evaluated by abnormal ancillary exercise scales, was either mildly or zeroly suppressed was SUN N4057 dose group (56%: 2nd day) ) Was significantly higher than the placebo group (0%: 2 days) (X = 0.02).

 In evaluation of Part 3 of the Parkinson's disease unification scale (UPDRS), in the placebo group, the 0.9 point decrease in comparison with the baseline in the placebo group was compared with the baseline in the SUN N4057 dosage group. In 4.4 points.

No adverse events and deaths of poisoning were seen in this study.

As described above, the results of clinical trials of SUN N4057 revealed the following.

A) The duration of efficacies (on time) of levodopa without Dyskinezia, the most preferred time in Parkinson's disease patients, increases after drug administration compared to baseline in the SUN N4057 dosing group, and this increase is also a placebo It was also large in comparison with the group.

B) The off time, which is the time when the effect of levodopa is insufficient and symptoms of Parkinson's disease (progression, constriction, motionlessness, postural reflex disorder) occurs, decreases after drug administration compared to baseline in the SUN N4057 dose group, and base in the placebo group. Increased after placebo administration compared to line.

C) SUN N4057 had a significant effect in interpreting respondents with an indicator of abnormality of movement scale (AIMS) and reduction of off time.

D) In the evaluation of Part 3 of the Parkinson's disease unification scale (UPDRS), the SUN N4057 dose group showed slightly higher improvement points compared to the placebo group.

Therefore, it has been found that SUN N4057 has a beneficial effect on the motor complications associated with levodopa treatment of Parkinson's disease.

Claims (24)

Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl, methoxy and halogen atoms Motor complications associated with levodopa treatment of Parkinson's disease, which comprises a compound substituted with or substituted with a phenyl group, a pyridyl group or a pyrimidinyl group, or a pharmacologically acceptable salt thereof or a hydrate thereof. To improve it. The compound of claim 1, wherein in formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, Or an unsubstituted pyridyl or pyrimidinyl group. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine -1-yl] butyl} -1,4-benzoxazepin-5-one. The medicament according to any one of claims 1 to 3, which reduces dyskinesia, an exercise complication associated with levodopa treatment of Parkinson's disease. The medicament according to any one of claims 1 to 3, wherein the levodopa treatment of Parkinson's disease is reduced in off time. The medicament according to any one of claims 1 to 3, wherein, in the treatment of levodopa in Parkinson's disease, the medicament duration (on time) of levodopa that does not involve dyskinesia is extended. The drug according to any one of claims 1 to 3, wherein the frequency of on / off symptoms of motor complications associated with levodopa treatment of Parkinson's disease is reduced. The medicament according to any one of claims 1 to 3, wherein the levodopa treatment of Parkinson's disease suppresses an increase in the therapeutically effective amount of levodopa accompanying the progression of symptoms. The medicament according to any one of claims 1 to 3, wherein in the treatment of levodopa in Parkinson's disease, the therapeutically effective daily dose of levodopa is reduced. Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl, methoxy and halogen atoms Inhibits or delays the progression of symptoms of Parkinson's disease, which is substituted with a compound or represented by an unsubstituted phenyl group, pyridyl group or pyrimidinyl group) or a pharmacologically acceptable salt thereof or a hydrate thereof. Letting medicine. The compound of claim 10, wherein in formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, Or an unsubstituted pyridyl or pyrimidinyl group. The compound of formula (I) according to claim 10, wherein the compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine -1-yl] butyl} -1,4-benzoxazepin-5-one. Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom and is substituted with one to three substituents selected from the group consisting of methyl, methoxy and halogen atoms. Development of motor complications associated with levodopa treatment of Parkinson's disease, or compounds containing a phenyl group, a pyridyl group, or a pyrimidinyl group, or a pharmacologically acceptable salt thereof or a hydrate thereof. Delaying medication. The compound of claim 13, wherein in formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, Z is substituted with a methyl group, Or an unsubstituted pyridyl or pyrimidinyl group. The compound of formula (I) according to claim 13, wherein the compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine -1-yl] butyl} -1,4-benzoxazepin-5-one. Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl, methoxy and halogen atoms Or a phenyl group, a pyridyl group or a pyrimidinyl group unsubstituted, or a pharmacologically acceptable salt thereof or a hydrate thereof. Drugs to improve. The compound of claim 16, wherein in formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, and Z is substituted with a methyl group Or an unsubstituted pyridyl group or pyrimidinyl group. The compound of claim 16, wherein the compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6-tetrahydropyridine -1-yl] butyl} -1,4-benzoxazepin-5-one. 19. The medicament according to any one of claims 16 to 18, wherein the psychotic symptoms associated with advanced stage Parkinson's disease are depression, anxiety or hallucinations. 20. The pharmaceutical composition according to any one of claims 1 to 19, comprising at least one agent selected from peripheral dopa decarboxylase inhibitors, monoamine oxidase B inhibitors, and catechol-O-methyl transferase inhibitors; A drug used in combination. (a) Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl groups, methoxy groups and halogen atoms A compound substituted with or represented by an unsubstituted phenyl group, a pyridyl group or a pyrimidinyl group) or a pharmacologically acceptable salt thereof or a hydrate thereof;
(b) levodopa
Parkinson's disease-containing pharmaceutical composition containing. (a) Formula (I),

(Wherein R ¹ represents a hydrogen atom, a chlorine atom or an alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, W represents a nitrogen atom, CH or a carbon atom, The dotted line indicates the absence of a bond when W is a nitrogen atom or CH, and the presence of a bond when W is a carbon atom, and Z is 1 to 3 substituents selected from the group consisting of methyl, methoxy and halogen atoms Substituted with or represented by an unsubstituted phenyl group, pyridyl group or pyrimidinyl group), or a pharmacologically acceptable salt thereof or a hydrate thereof,
(b) levodopa,
(c) A pharmaceutical composition for treating Parkinson's disease containing one or more drugs selected from peripheral dopa decarboxylase inhibitors, monoamine oxidase B inhibitors and catechol-O-methyl transferase inhibitors. The chemical formula (I) according to claim 21 or 22, wherein in formula (I), R ¹ represents a chlorine atom, R ² represents a hydrogen atom, W represents a carbon atom, a dotted line represents the presence of a bond, and Z represents a methyl group. A composition which represents a pyridyl group or a pyrimidinyl group substituted by or unsubstituted. 23. The compound of claim 21 or 22, wherein the compound of formula (I) is 3-chloro-4,5-dihydro-4- {4- [4- (2-pyridyl) -1,2,3,6 -Tetrahydropyridin-1-yl] butyl} -1,4-benzoxazepin-5-one.

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